CN101801958A

CN101801958A - Heterocyclic amide as protein kinase inhibitors

Info

Publication number: CN101801958A
Application number: CN200880106656A
Authority: CN
Inventors: P·A·P·雷迪; 赵联运; P·K·塔迪康达; T·T·王; S·唐; L·E·托里斯; D·F·小考布尔; T·J·古奇; M·A·西迪奎
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2007-07-19
Filing date: 2008-07-17
Publication date: 2010-08-11
Anticipated expiration: 2028-07-17
Also published as: WO2009014637A2; CO6290765A2; RU2010105678A; CL2008002131A1; AU2008279776A1; PE20090905A1; JP2010533716A; TWI371275B; EP2178861A2; KR101552742B1; WO2009014637A3; CA2693967A1; AR067585A1; RU2474580C2; NZ582708A; ECSP109886A; EP2178861B1; TW200920370A; BRPI0814441A2; ZA201000366B

Abstract

The present invention relates to as formula I heterocyclic amide disclosed herein:

Description

Heterocyclic amide as protein kinase inhibitors

Invention field

The present invention relates to can be used as the compound that protein kinase inhibitors, conditioning agent or modulator use, the medical composition that contains this compounds, and the treatment various diseases method of using this compounds and composition, described disease for example: cancer, inflammation, sacroiliitis, virus disease, neurodegenerative disease for example Ah ear are grown extra large Mo's disease, cardiovascular disorder and fungal disease.

Background technology

Protein kinase is a kind of enzyme family, the hydroxyl of specific tyrosine, Serine or threonine residues in the phosphorylated effect, particularly protein of its meeting catalytic proteins.Protein kinase is the hinge of the adjusting of many kinds of cell processes, and described cell processes comprises metabolism, hyperplasia, cytodifferentiation and cell survival.Uncontrolled hyperplasia is the sign of cancer cells, and one of can be in two ways imbalance by cell division cycle prove-cause pungency gene hyperactivity hyperkinesia or Inhibit Genes inactivation.Protein kinase inhibitors, conditioning agent or modulator can change kinase whose function, for example cyclin-dependent kinase (CDK), mitogen activation of protein kinases (MAPK/ERK), glycogen synthase kinase 3 (GSK3 β), check point (Chk) kinases (for example CHK-1, CHK-2 etc.), AKT kinases, PDK-1, JNK etc.The example of protein kinase inhibitors in WO 02/22610A1, and by people such as Y.Mettey in J.Med.Chem., 46: describe among the 222-236 (2003).

Cyclin-dependent kinase is a serine/threonine protein matter kinases, and it is cell cycle and hyperplasia motivating force behind.The mistake of CDK function is adjusted in many important noumenal tumours and takes place with high frequency.Indivedual CDK, for example CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8 etc. have given play to unique effect in the cell cycle progress, and can be classified as be G1S or G2M phase enzyme.CDK2 and CDK4 make us interested especially, because of its activity is regulated by wrong in many kinds of human cancers continually.The CDK2 activity is needed through the process of G1 to the S phase of cell cycle, and CDK2 is one of crucial composition of G1 check point.The check point is in order to the correct order of maintenance cell cycle incident, and the permission cell takes place yet the forfeiture that suitable check point is controlled in the cancer cells can encourage tumour invading or the hyperplasia signal being had response.The CDK2 approach can take place in the level affects tumour of tumor suppressor gene function (for example p52, RB and p27) with oncogene activation (plain E of cycle).Many reports confirm, plain E of the coactivator cycle of CDK2 and inhibitor p27, both excessively or insufficiently are expressed in mastocarcinoma, colorectal carcinoma, nonsmall-cell lung cancer, cancer of the stomach, prostate cancer, bladder cancer, non-Hodgkin lymphomas, ovarian cancer and other cancer respectively.Their expression through changing has been proved with the CDK2 level of activity and the bad overall survival that increase interrelated.This observation makes CDK2 and adjusting approach thereof become noticeable target in the exploitation of cancer therapy medicine.

Competitive little organic molecule of many adenosine 5'-triphosphates (ATP) and peptide are reported the CDK inhibitor as the potential treatment of cancer in the literature.U.S.6,413,974 the 23rd row-Di 15 hurdles the 10th, the 1st hurdle row provide various CDK and with the good description of the relation of various cancer types.Flavones pyridine alcohol (Flavopiridol, hereinafter shown in) is a kind of non-selective CDK inhibitor, and it is carrying out human clinical trial, A.M.Sanderowicz et al., J.Clin.Oncol. at present 16: 2986-2999 (1998).

The known inhibitor of other of CDK, for example comprise olomoucine (olomoucine) (J.Veselyet al., Eur.J.Biochem., 224: 771-786 (1994)) but with Loews Wei Ting (roscovitine) (l.Meijer et al., Eur.J.Biochem., 243: 527-536 (1997)).U.S.6,107,305 have described some pyrazolo as the CDK inhibitor [3,4-b] pyridine compounds.The illustrative of compounds of a kind of deriving from ' 305 patents is:

K.S.Kim et al., J.Med.Chem. 45: 3905-3927 (2002) and WO 02/10162 disclose some aminothiazole compounds as the CDK inhibitor.

Another serial protein kinase is to play the part of one as those of the key player of check point in cell cycle progress.The check point can prevent that cell cycle from making progress under the inappropriate time, for example respond the DNA injury, and the metabolic balance that when cell is contained, keeps cell, and in some cases, when the requirement condition of check point is not satisfied as yet, can cause apoptosis (apoptosis).Check point control can occur in the G1 phase (before DNA is synthetic) and in G2, in entering mitotic division before.

Genomic integrity can be monitored in a series of check points, and when sensing DNA injured, this type of " DNA injures the check point " can be at G ₁And G ₂Interim blocking-up cell cycle is made progress, and slows down the progress through the S phase.This effect make the DNA mending course can the producer group duplicate and the later separation of this genetic stew is finished its work before to the new daughter cell.The inactivation of CHK1 has been proved and can transduction have injured the signal of feeling mixture from DNA-, with the kinase whose activation of plain B/Cdc2 of inhibition cycle, it can promoting mitosis enters, and eliminates the G that the DNA that the applies injury brought out because of carcinostatic agent or the injury of interior source DNA is caused ₂The containment, and can cause preferentially kill the damaged cell in the check point that forms.Consult, for example, Peng et al., Science, 277: 1501-1505 (1997); Sanchez et al., Science, 277: 1497-1501 (1997), Nurse, Cell, 91: 865-867 (1997); Weinert, Science, 277: 1450-1451 (1997); Walworth et al., Nature, 363: 368-371 (1993); With AI-Khodairy et al., Molec.Biol.Cell., 5: 147-160 (1994).

The selectivity of check point control is controlled in cancer cells, can make to provide in the usage widely in cancer chemotherapeutic and radiotherapy and use, and the common sign of human cancer " genomic instability " can be provided in addition, and it is to desire to be developed the selectivity basis of destroying as cancer cells.The multiple factor is positioned over CHK1 on the maincenter target in the control of DNA-injury check point.This kind and functional go up associated kinase for example CDS1/CHK2 (kinases that the S phase makes progress is regulated in a kind of recent findings meeting and CHK1 cooperation) (consult Zeng et al., Nature, 395: 507-510 (1998); Matsuoka, Science, 282: the explanation of inhibitor 1893-1897 (1998)) can provide the cancer therapy entity of valuable novelty.

Another group kinases is a Tyrosylprotein kinase.Tyrosylprotein kinase can be acceptor type (have born of the same parents outer, stride functional part in film and the born of the same parents) or non-acceptor type (being entirely in the born of the same parents).The acceptor type Tyrosylprotein kinase comprises a large amount of transmembrane receptors, has various biologic activity.In fact, about 20 kinds of different subtribes of acceptor type Tyrosylprotein kinase are identified.A kind of Tyrosylprotein kinase subtribe of the HER of being called subtribe comprises EGFR (HER1), HER2, HER3 and HER4.The ligand of this acceptor subtribe through confirming comprises epidermal growth factor, TGF-α, the two-ways regulation factor, HB-EGF, β cytokine (betacellulin) and heredity plain (heregulin) extremely so far.Another subtribe of this type of acceptor type Tyrosylprotein kinase is the Regular Insulin subtribe, and it comprises INS-R, IGF-IR, IR and IR-R.The PDGF subtribe comprises PDGF-α and beta receptor, CSFIR, c-kit and FLK-II.FLK family comprises that kinases inserts functional part acceptor (KDR), fetus liver kinases-1 (FLK-1), fetus liver kinases-4 (FLK-4) and like fms Tyrosylprotein kinase-1 (flt-1).About going through of acceptor type Tyrosylprotein kinase, can consult Plowman et al., DN﹠amp; P 7 (6): 334-339,1994.

It is believed that at least a non-receptor protein tyrosine kinases, meaning is LCK, can mediate from cell surface proteins (Cd4) to resist-transduction of the interactive signal of Cd4 antibody in the T-cell with crosslinked.More going through of nonreceptor tyrosine kinase is provided in Bolen, oncogene, 8: among the 2025-2031 (1993).The non-acceptor type of Tyrosylprotein kinase also comprises many subtribes, comprises Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK.Each this type of subtribe further is divided into not isoacceptor again.For example, the Src subtribe is a kind of of maximum, and comprises Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.The Src subtribe of enzyme has been linked to and has been tied to the tumour generation.About more going through of the non-acceptor type of Tyrosylprotein kinase, can consult Bolen, oncogene, 8: 2025-2031 (1993).

Except the effect of protein kinase in cell cycle control, it also plays the part of a decisive role in vasculogenesis, and it is for passing through from the existing new microvascular mechanism of vascularization.When needs, this vascular system has the possibility that produces new capillary blood vessel network, to keep the suitable function of tissue and organ.But in the adult, vasculogenesis is considerably limited, occurs over just the process of wound healing, and in the endometrial neovascularity nucleus formation of intermenstrual period.On the other hand, the vasculogenesis of not expecting is the sign of several conditions, described disease for example retinopathy, psoriasis, rheumatoid arthritis, with aging relevant macular degeneration and cancer (noumenal tumour).Be proved the protein kinase that relates to angiogenesis, comprised three members of growth factor receptor tyrosine kinase family; (vascular endothelial growth factor receptor 2 also is called KDR (kinases insert functional part acceptor) and FLK1) to VEGF-R2; FGF-R (fibroblast growth factor acceptor); And TEK (also being called Tie-2).

The VEGF-R2 that only is expressed on the endotheliocyte can be in conjunction with effective blood vessel protogrowth factor VEGF, and through the active activation of its intracellular kinase, the mediation follow-up signal is transduceed.Therefore, the direct inhibition of expection VEGF-R2 kinase activity will cause the reduction vasculogenesis, even also like this in the presence of exogenous VEGF (consult Strawn et al, Cancer Res., 56: 3540-3545 (1996)), it confirms that with the mutant of VEGF-R2 it fails to mediate signal transduction.Millauer?et?al，Cancer?Res.， 56：1615-1620(1996)。In addition, VEGF-R2 is presented among the adult, except the angiogenic activity of mediation VEGF, does not have function.Therefore, the selective depressant of expection VEGF-R2 kinase activity can show extremely low toxicity.

Similarly, FGFR can be in conjunction with blood vessel protogrowth factor aFGF and bFGF, and mediates follow-up intracellular signal transduction.Recently, existing people points out somatomedin, and for example bFGF can play the part of a pivotal player in causing vasculogenesis in the noumenal tumour that reaches a certain size.Yoshiji?et?al.，Cancer?Research， 57：3924-3928(1997)。But different with VEGF-R2, FGF-R is expressed in the multiple different cell type at whole body, and can or can not play an important role in other normal physiological processes of adult.Even so, the systemic administration of the micromolecular inhibitor of FGF-R kinase activity is reported that the blocking-up vasculogenesis that bFGF caused does not have tangible toxicity in mouse.Mohammad?et?al.，EMBOJournal， 17：5996-5904(1998)。

TEK (also being called Tie-2) is the another kind of receptor tyrosine kinase that only is expressed on the endotheliocyte, and it has been proved plays the part of a role in vasculogenesis.The combination of factor angiogenin-1 can cause TEK the kinase function position from the phosphorylated effect, and can cause the signal transduction process, it shows can mediation endotheliocyte and the interaction of endothelium sustenticular cell on every side, thereby helps Neovascularized maturation.On the other hand, factor angiopoietin-2 shows and can generate plain-1 effect for TEK by antagonizing vessel, and disintegrates vasculogenesis.Maisonpierre?et?al.，Science， 277：55-60(1997)。

Kinases JNK belongs to mitogen activation of protein kinases (MAPK) superfamily.JNK plays the part of a decisive role on inflammatory response, stress response, hyperplasia, apoptosis and tumour take place.The JNK kinase activity can be activated by various stimulations, comprises that costimulatory receptor (CD28 and CD40), DNA-nocuity chemical, radiation and Fas send signal altogether for proinflammatory cytokine (TNF-α and interleukin 1), lymphocyte.The result who derives from the disallowable mouse of JNK shows that JNK relates to apoptosis and brings out with t helper cell and break up.

Pim-1 is little serine/threonine kinase.The high expression level degree of Pim-1 is detected in lymph sample and marrow sample malignant disorders, and recently, Pim-1 is through confirming as the prognostic markers thing in prostate cancer.K.Peltola, " Signaling in Cancer:Pim-1 Kinase and itsPartners ", Annales Universitatis Turkuensis, Sarja-Ser.D Osa-Tom.616, (on August 30th, 2005), Http:// kirjasto.utu.fi/julkaisupalvelut/annaalit/2004/D616.htmlPim-1 uses liability factor as, and can prevent the apoptosis in the malignant cell.K.Petersen?Shay?etal.，Molecular?Cancer?Research? 3：170-181(2005)。

(aurora body-A, aurora body-B, aurora body-C) are serine/threonine protein matter kinases to aurora body kinases, and for example colorectal carcinoma, mastocarcinoma and other noumenal tumour are relevant with human cancer for they.It is believed that aurora body-A (also being called as AIK sometimes) is relevant with the protein phosphorylated incident of regulating cell cycle.Specifically, aurora body-A can play the part of a role on the chromosomal clean cut separation of control during mitotic division.The mistake of cell cycle is regulated and may be caused hyperplasia and other unusual.In cancerous human colon tumor tissue, found aurora body-A, aurora body-B, aurora body-C by overexpression (consult Bischoff et al., EMBO J., 17: 3052-3065 (1998); Schumacher et al., J.Cell Biol. 143: 1635-1646 (1998); Kimura et al., J.Biol.Chem., 272: 13766-13771 (1997)).

C-Met is a kind of former Oncogene, their coding pHGF/dispersion factors (HGF/SF) Tyrosylprotein kinaseAcceptor.C-Met albumen is mainly expressed in epithelial cell, and because its function, it also is called hepatocyte growth factor receptor or HGFR.When HGF/SF activation c-Met, the latter can activate many kinase pathway successively, comprise from RasExtremely RafTo Mek to the mitogen activatory Protein kinaseERK1 is to the path of transcription factor ETS1.Met signal the nosetiology related to human cancer and pernicious process (referring to Birchmeier et al., NatureReviews Molecular Cell Biology, 4:915-925 (2003); Zhang et al., Journalof Cellular Biochemistry, 88: 408-417 (2003); And Paumelle et al., oncogene, 21: 2309-2319 (2002)).

Kinase whose AGC subtribe is at Serine and threonine residues place their substrate of phosphorylation; and participate in many known signalling processes; include but not limited to control (the Peterson et al. of cAMP signalling, response, apoptosis protection, DG signalling and protein translation to Regular Insulin; Curr.Biol.1999; 9, R521).This subtribe comprises PKA, PKB (c-Akt), PKC, PRK1,2, p70 ^S6KWith PDK

AKT (also being called PKB or Rac-PK β), a kind of serine/threonine protein matter kinases has shown that its cross to express in the cancer of some types, and is that [(Nature 1999,401,33-34) for Khwaja, A. for the conditioning agent of normal cell function; (Yuan, Z.Q., et al., oncogene 2000,19,2324-2330); (Namikawa, K., et al., J.Neurosci.2000,20,2875-2886)].AKT comprise the terminal pleckstrin homology of N-(pleckstrinhomology, PH) zone, kinases is regional and C-terminal " afterbody " zone.The kinase whose three kinds of hypotypes of people AKT (AKT-1 ,-2 and-3) up to the present are in the news, and [(Proc.Natl.Acad.Sci.USA 1992,89,9267-9271) for Cheng, J.Q.; (Brodbeck, D.et al., J.Biol.Chem.1999,274,9133-9136)].The PH zone is in conjunction with the 3-phosphoinositide, it is synthetic by phosphatidyl-inositol 3-kinase when factors stimulated growth, described somatomedin is phosphatidylinositols (PDGF), nerve growth factor (NGF) and rhIGF-1 (IGF-1) [(Kulik et al. for example, Mol.Cell.Biol., 1997,17,1595-1606); (Hemmings, B.A., Science, 1997,275,628-630)].Promoted AKT to translocate to cytoplasmic membrane with PH zone bonded lipid, and promoted phosphorylation by the protein kinase that contains another PH-zone, for AKT hypotype 1,2 and 3 respectively at Thr308, Thr309 and the Thr305 place of PDK1.Secondly, still unclearly be that in order to produce complete activatory AKT enzyme, for respectively in AKT-1 ,-2 and-3 the terminal afterbody of C-, Ser473, Ser474 or Ser472 and phosphorylation need kinases.

In case focus on the film, AKT can mediate some functions in cell, the metabolism (Calera, M.R.et al., the J.Biol.Chem.1998 that comprise Regular Insulin, 273,7201-7204), differentiation and/or outgrowthly induce, albumen is synthetic and stress respond (Alessi, D.R.et al., Curr.Opin.Genet.Dev.1998,8,55-62).

In damage and disease, all show the evidence of the AKT adjusting of change, most important acting in the cancer.AKT first the explanation be relevant with human ovarian cancer, wherein the expression of AKT have 15% case increase (Cheng, J.Q.et al., Proc.Natl.Acad.Sci.U.S.A.1992,89,9267-9271).Find that also expression was arranged in 12% carcinoma of the pancreas (Cheng, J.Q.et al., Proc.Natl.Acad.Sci.U.S.A.1996,93,3636-3641).Confirm that AKT-2 cross to express, and the increase of AKT is very common in 50% not differentiation tumor in 12% ovarian cancer, show AKT also may be relevant with tumor invasion (Int.J.Cancer 1995,64,280-285) for Bellacosa, et al..

PKA (also being called cAMP-dependence protein matter kinases) has shown the many vital functions of adjusting, comprise energy metabolism, genetic transcription, hyperplasia, differentiation, copy function, secretion, nervous activity, memory, retractility and motility (Beebe, S.J., Semin.Cancer Biol.1994,5,285-294).PKA is a kind of tetramer holoenzyme, and it contains and homodimer regulator subunit (its performance suppresses the effect of catalytic subunit) two catalytic subunits of bonded.In conjunction with cAMP the time (enzyme activation), separate from regulator subunit in this catalytic subunit, generation activatory serine/threonine kinase (McKnight, G.S.et al., Recent Prog.Horm.Res.1988,44, pp.307).The existing so far report (Beebe of three kinds of hypotypes of this catalytic subunit (C-α, C-β and C-γ), S.J.et al., J.Biol.Chem.1992,267,25505-25512), the C-alpha subunit is for studying the most widely, mainly be that (Oncogene 1990 for Becker, D.et al. owing to its high expression level in primary and metastatic melanoma, 5,1133).Up to the present, regulating the active strategy of C-alpha subunit comprises use antibody, blocks active molecule of PKA and antisense oligonucleotide expression by target adjusting dimer.

Ribosomal protein kinases p70 ^S6K-1 and-2 also is the member of the AGC subtribe of protein kinase, and phosphorylation and the follow-up activation of this ribosomal protein of catalysis S6, and this ribosomal protein S6 is relevant with the translation adjusted of the mRNA of the component of proteins encoded composite structure.These mRNA contain few pyrimidine (oligopyrimidine) passage at their 5 ' transcription initiation site, be called 5 ' TOP, it has shown that be essential (Volarevic for them in the adjusting of translation skill, S.et al., Prog.Nucleic Acid Res.Mol.Biol.2001,65,101-186).P70 ^S6KDependency S6 phosphorylation in to multiple mainly hormone by the PI3K path and somatomedin response, be upset (Coffer, P.J.et al., Biochem.Biophys.Res.Commun, 1,994 198,780-786), it may be below the adjusting of mTOR, because the rapamycin performance suppresses p70 ^S6KActive and blocking protein synthetic effect, particularly since the following adjusting of the translation of the mRNA of these coding ribosomal proteins (Nature 1992,358,70-73) for Kuo, C.J.et al..

External PDK1 catalysis the phosphorylation of the Thr252 in the activation ring of p70 catalytic domain, this p70 catalytic domain for p70 activation be absolutely necessary (Alessi, D.R., Curr.Biol., 1998,8,69-81).The application of rapamycin and established the vital role of p70 in cell growth and hyperplasia signalling from the dp70S6K of Drosophila with from the genetically deficient research of the dp70S6K of mouse.

3-phosphoinositide-dependence protein matter kinases-1 (PDK1) is brought into play keying action (Biochem.Soc.Trans 2001,29 for Alessi, D.et al., 1) in the kinase whose activity of regulating many AGC subtribes that belong to protein kinase.These comprise Protein Kinase B hypotype (PKB also is called AKT), p70 ribosome S 6 kinases (S6K) (Avruch, J.et al., Prog.Mol.Subcell.Biol.2001,26,115) and p90 ribosome S 6 kinases (Frodin, M.et al., EMBO J.2000,19,2924-2934).The signalling of PDK1 mediation is activated in the response to Regular Insulin and somatomedin, causes cell and extracellular matrix to adhere to (integrin signalling).In case be activated, these enzymes mediate many different cellular events by making the crucial protein phosphorylation of regulating, described adjusting albumen in control example such as the glycoregulatory process of cell survival, growth, hyperplasia and grape, play a significant role [(Lawlor, M.A.et al., J.Cell Sci.2001,114,2903-2910), (Lawlor, M.A.et al., EMBO are J.2002,21,3728-3738)].PDK1 is a kind of 556 amino acid whose albumen, has terminal catalytic domain of N-and the terminal pleckstrin homology (PH) of C-zone, and it makes these tyrosine phosphorylations activate its substrate (Belham by the activation ring at them, C.et al., Curr.Biol.1999,9, R93-R96).Many human cancers comprise that prostate cancer and NSCL have improved PDK1 signalling channel function, described function results from many different genetic events, and for example PTEN sudden change and some are crucial regulates proteic the mistake and express [(Graff, J.R., Expert Opin.Ther.Targets 2002,6,103-113), (Brognard, J., et al., Cancer Res.2001,61,3986-3997)].Confirmed with the directed transfection that suppresses the antisense oligonucleotide of PDK1 by PTEN negativity human carcinoma cell line (U87MG) as the PDK1 restraining effect of a kind of potential mechanism with the treatment cancer.The minimizing that reduces to cause hyperplasia and survival that causes on the PDK1 protein level (Flynn, P., et al., Curr.Biol.2000,10,1439-1442).Therefore, in other treatment, the cancer chemotherapeutic that is designed to of the ATP-binding site inhibitor of PDK1 provides noticeable target.

The cancer cells genotype of different range is by owing to the following six kinds of basic performance patterns that change in the stechiology: self-sufficient, the apoptotic escape in growth is signaled, to growth-inhibiting signal insensitive, the possibility of infinite copy, lasting vasculogenesis and the tissue invasion and attack (Hanahan that causes transfer, D.et al., Cell 2000,100,57-70).PDK1 is the crucial conditioning agent of PI3K signalling passage, and its adjusting comprises many cell functions of growth, hyperplasia and survival.As a result, for the cancer process, the restraining effect of this passage may influence four kinds of demand of these six kinds of definition or more.Like this, expection PDK1 inhibitor will influence the growth of the human cancer in the unusual wide region.

Especially, the level of P13K channel activity increases directly relevant with the process and the prognosis mala of the development of many human cancers, aggressive refractory state (to chemotherapeutical acquired tolerance).The activity of this increase is by owing to a series of critical event, comprise for example activity reduction of phosphoesterase PTEN of negativity channel modulators, the positivity channel modulators is the activation sudden change of Ras for example, and for example expression excessively of PKB of the component of passage own, example comprises: brain (neurospongioma), mammary gland, colon, head and neck, kidney, lung, liver, melanoma, ovary, pancreas, prostate gland, sarcoma, Tiroidina [(Teng, D.H.et al., Cancer Res., 1,997 57,5221-5225), (Brognard, J.et al., Cancer Res., 2001,61,3986-3997), (Cheng, J.Q.et al., Proc.Natl.Acad.Sci.1996,93,3636-3641), (Int.J.Cancer 1995,64,280), (Graff, J.R., Expert Opin.Ther.Targets 2002,6,103-113), (Am.J.Pathol.2001,159,431)].

In addition, gene knockout by this passage, gene beats (knockdown), research of dominance negative and micromolecular inhibitor and the channel function that reduces have been proved and can have reversed many external cancerous phenotypes (some research also is proved similar action in vivo), for example in a series of clones, block hyperplasia, reduce survival rate and make cancer cells responsive to known chemical treatment, representational have a following cancer: carcinoma of the pancreas [(Cheng, J.Q.et al., Proc.Natl.Acad.Sci.1996,93,3636-3641), (Neoplasia 2001,3,278)], lung cancer [(Brognard, J.et al., CancerRes.2001,61,3986-3997), (Neoplasia 2001,3,278)], ovarian cancer [(Hayakawa, J.et al., Cancer Res.2000,60,5988-5994), (Neoplasia 2001,3,278)], mammary cancer (Mol.Cancer Ther.2002,1,707), colorectal carcinoma [(Neoplasia 2001,3,278), (Arico, S.et al., J.Biol.Chem.2002,277,27613-27621)], (Neoplasia 2001 for the neck cancer, 3,278), [(Endocrinology 2001,142 for prostate cancer, 4795), (Thakkar, H.et al.J.Biol.Chem.2001,276,38361-38369), (Oncogene 2001 for Chen, X.etal., 20,6073-6083)] and the cancer of the brain (glioblastoma) [(Flynn, P.etal., Curr.Biol.2000,10,1439-1442)].

The multiple p38 MAPK-dependent cell of mitogen-activatory-protein kinase-activatory protein kinase 2 (MAPKAP K2 or MK2) mediation is replied.MK2 is the conditioning agent that a kind of important cell within a cell factor generates, this cytokine is tumor necrosis factor alpha (TNFa), interleukin 6 (IL-6) and interferon-gamma (IFNg) for example, and they are with many acute for example rheumatoid arthritis is relevant with inflammatory bowel with chronic inflammatory disease.MK2 is arranged in the nuclear of non-irritation cell, and when stimulating, its transposition is in tenuigenin, and phosphorylation and activation tuberin (tuberin) and HSP27.MK2 also damages with heart failure, cerebral ischaemia, stress resistance regulate relevant (referring to Deak et al., EMBO. with the generation of TNF-α 17: 4426-4441 (1998); Shi et al., Biol.Chem. 383: 1519-1536 (2002); Staklatvala., Curr.Opin.Pharmacol. 4: 372-377 (2004); And Shiroto et al., J.Mol.CellCardiol. 38: 93-97 (2005)).

International open WO 2005/115146 relates to bridged piperazine derivatives and their purposes in Pest Control.

International open WO 2004/002948 relates to amide compound, and they can effectively suppress the interleukin 4 generation in 2 type helper cell, can be used as bradykinin (bradykinin) B1 receptor antagonism.International open WO 2003/045921 relates to the heterocyclic amide as the apolipoprotein B inhibitor.All the U.S. Provisional Application sequence number of submitting on October 31st, 2,006 60/855,421 and 60/855,422 relates to anilino bridged piperazine derivatives and using method thereof.The U. S. application sequence number of submitting on June 5th, 2,007 11/758,243 relates to the Imidazopyrazine as protein kinase inhibitors.

In order to treat or prevention and abnormal cells hyperplasia disease states associated, need the kinase whose inhibitor of effective protein proteins matter.In addition, have at the high-affinity of target kinase and be desirable the kinase inhibitor of other protein kinase highly selective.Can synthesize easily and be that the micromolecular compound of effective inhibitor of hyperplasia is for example following those, they are one or more inhibitors of protein kinases, and this kinases is CHK1, CHK2, VEGF (VEGF-R2), Pim-1, PDK-1, CDKs or CDK/ cyclin mixture and acceptor and nonreceptor tyrosine kinase for example.

Summary of the invention

In many embodiments, the invention provides the heterocyclic amide of novel kind, comprise the medical composition of one or more these compounds, and the method for using this compounds for treating or prevention proliferative disease, anti-hyperplasia illness, inflammation, sacroiliitis, neuroscience or neurodegenerative disease, cardiovascular disorder, alopecia, sacred disease, local asphyxia damage, virus disease or fungal disease.

For this reason, in one aspect, the invention provides formula (I) compound:

Formula I

Or its pharmacologically acceptable salts or ester; Wherein:

Ring A is selected from aryl and heteroaryl, wherein when each described aryl and heteroaryl had two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form 5-to 6-unit aryl, heterocyclic radical, heterocycloalkenyl or heteroaryl ring;

M is N or N-oxide compound;

X, Y and Z are independently selected from N, N-oxide compound and C (R), and condition is that only to be no more than 1 among X, Y and the Z can be N or N-oxide compound;

T be O, S or-NR ⁴

Each R be independently selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, heterocycloalkenyl, aryl, heteroaryl ,-NR ⁴R ⁵, hydroxyl, alkoxyl group ,-SR ⁴,-S (=O) R ⁴,-S (=O) ₂R ⁴,-C (=O) R ⁴,-C (=O) OR ⁴,-C (=O) NR ⁴R ⁵,-C (=O) NR ⁴S (=O) ₂R ⁴,-C (=O) NR ⁴S (=O) ₂R ⁴,-C (=O) NR ⁴S (=O) ₂NR ⁴R ⁵,-C (=O) NR ⁴S (=O) ₂NR ⁴R ⁵,-C (=O) NR ⁴S (=O) ₂NR ⁴R ⁵,-S (=O) ₂R ⁴R ⁵,-S (=O) R ⁴R ⁵,-S (=O) ₂NR ⁴R ⁵,-S (=O) ₂OR ⁴,-NR ⁴C (=O) NR ⁴R ⁵,-NR ⁴C (=O) R ⁴,-NR ⁴C (=O) OR ⁴,-NR ⁴S (=O) ₂NR ⁴R ⁵,-NR ⁴S (=O) ₂NR ⁴R ⁵C (=O) NR ⁴R ⁵,-NR ⁴OR ⁴With-NR ⁴NR ⁴R ⁵

R ¹Be selected from-C (=O) N (R ⁴) aryl ,-C (=O) N (R ⁴) heteroaryl ,-C (=O) N (R ⁴) heterocyclic radical ,-C (=O) N (R ⁴) heterocycloalkenyl ,-N (R ⁴) C (=O) aryl ,-N (R ⁴) C (=O) heteroaryl ,-N (R ⁴) C (=O) heterocyclic radical ,-N (R ⁴) C (=O) heterocycloalkenyl ,-N (R ⁴) C (=O) N (R ⁴) aryl, aryl, heterocyclic radical, heterocycloalkenyl and heteroaryl, wherein each R ¹Heterocyclic radical, heterocycloalkenyl and heteroaryl contain at least one azo-cycle atom, and wherein as each R ¹Heterocyclic radical, heterocycloalkenyl, aryl, heteroaryl, and-C (=O) N (R ⁴) aryl ,-C (=O) N (R ⁴) heteroaryl ,-C (=O) N (R ⁴) heterocyclic radical ,-C (=O) N (R ⁴) heterocycloalkenyl ,-N (R ⁴) C (=O) aryl ,-N (R ⁴) C (=O) heteroaryl ,-N (R ⁴) C (=O) heterocyclic radical and-N (R ⁴) C (=O) heterocycloalkenyl should " heterocyclic radical ", " heterocycloalkenyl ", when " aryl " and " heteroaryl " part has two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form the first cycloalkyl of 5-to 6-, cycloalkenyl group, aryl, heterocyclic radical, heterocycloalkenyl or heteroaryl ring;

R ²Be H or alkyl;

R ³Be selected from heterocyclic radical, heterocycloalkenyl, aryl, heteroaryl ,-OR ⁴,-SR ⁴,-S (=O) R ⁴,-S (=O) ₂R ⁴With-NR ⁴R ⁵

Each R ⁴And R ⁵Be independently selected from H, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, heterocycloalkenyl, aryl and heteroaryl;

Condition is to work as R ¹When being morpholinyl, R be different from the optional alkoxyl group that replaces or optional replace-N (alkyl) ₂

On the other hand, the invention provides formula (I) compound:

Formula I

Or its pharmacologically acceptable salts or ester; Wherein:

M is N or N-oxide compound;

T be O, S or-NR ⁴

R ¹Be selected from-C (=O) N (R ⁴) aryl ,-C (=O) N (R ⁴) heteroaryl ,-C (=O) N (R ⁴) heterocyclic radical ,-C (=O) N (R ⁴) heterocycloalkenyl ,-N (R ⁴) C (=O) aryl ,-N (R ⁴) C (=O) heteroaryl ,-N (R ⁴) C (=O) heterocyclic radical ,-N (R ⁴) C (=O) heterocycloalkenyl, aryl, heterocyclic radical, heterocycloalkenyl and heteroaryl, wherein each R ¹Heterocyclic radical, heterocycloalkenyl and heteroaryl contain at least one azo-cycle atom, and wherein as each R ¹Heterocyclic radical, heterocycloalkenyl, aryl, heteroaryl, and-C (=O) N (R ⁴) aryl ,-C (=O) N (R ⁴) heteroaryl ,-C (=O) N (R ⁴) heterocyclic radical ,-C (=O) N (R ⁴) heterocycloalkenyl ,-N (R ⁴) C (=O) aryl ,-N (R ⁴) C (=O) heteroaryl ,-N (R ⁴) C (=O) heterocyclic radical and-N (R ⁴) C (=O) heterocycloalkenyl should " heterocyclic radical ", " heterocycloalkenyl ", when " aryl " and " heteroaryl " part has two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form the first cycloalkyl of 5-to 6-, cycloalkenyl group, aryl, heterocyclic radical, heterocycloalkenyl or heteroaryl ring;

R ²Be H or alkyl;

In one aspect, formula I compound can be used as the protein kinase inhibitors use.

On the other hand, formula I compound can be used for treatment or prevention proliferative disease, anti-hyperplasia illness, inflammation, sacroiliitis, neuroscience or neurodegenerative disease, cardiovascular disorder, alopecia, sacred disease, local asphyxia damage, virus disease or fungal disease (being respectively a kind of " state of an illness ").

On the other hand, the invention provides medical composition, it comprises at least a formula I compound and pharmaceutically acceptable carrier.Said composition can be used for treating or preventing patient's the state of an illness.

More on the other hand, the invention provides the method for treatment patient's the state of an illness, this method comprises at least a formula I compound of using significant quantity to the patient.

On the other hand, the invention provides treatment patient method for cancer, this method comprises to the patient to be used at least a formula I compound of significant quantity and at least aly not to be the other carcinostatic agent of formula I compound.

Detailed Description Of The Invention

In one embodiment, the invention provides formula (I) compound and/or its pharmacologically acceptable salts, solvate, ester and prodrug.Formula I compound can be used for treating or preventing patient's the state of an illness.

When being used in when above reaching whole present disclosure, following term, unless point out in addition, otherwise should understand to have following meaning:

" patient " comprises human and animal.

Human and other Mammals of " Mammals " expression.

" alkyl " expression aliphatic hydrocarbyl, it can be straight or branched, and comprise about 1 to about 20 carbon atoms in this chain.Preferred alkyl contain have an appointment 1 to about 12 carbon atoms in this chain.Preferred alkyl contain have an appointment 1 to about 6 carbon atoms in this chain.Side chain is represented one or more low alkyl groups, and for example methyl, ethyl or propyl group are connected to linear alkyl chain." low alkyl group " expression have about 1 to the group of about 6 carbon atoms in this chain, it can be straight or branched." alkyl " can not be substituted, or optional can be identical or different substituting group and replace by one or more, each substituting group be independently selected from halogen, alkyl, aryl, cycloalkyl, heterocyclic radical, heteroaryl, cyano group, hydroxyl, alkoxyl group, alkylthio, amino ,-NH (alkyl) ,-NH (cycloalkyl) ,-N (alkyl) ₂,-O-C (O)-alkyl ,-O-C (O)-aryl ,-O-C (O)-cycloalkyl, carboxyl and-C (O) O-alkyl.Suitably the limiting examples of alkyl comprise methyl, ethyl, just-propyl group, sec.-propyl and the tertiary butyl.

" thiazolinyl " expression contains the aliphatic hydrocarbyl of at least one carbon-to-carbon double bond, and it can be straight or branched, and comprise about 2 to about 15 carbon atoms in this chain.Preferred thiazolinyl have about 2 to about 12 carbon atoms in this chain; And be more preferably about 2 to about 6 carbon atoms in this chain.Side chain is represented one or more low alkyl groups, and for example methyl, ethyl or propyl group are connected to linear alkenylene chain." low-grade alkenyl " expression about 2 to about 6 carbon atoms in this chain, it can be straight or branched." thiazolinyl " can not be substituted, or optional can be identical or different substituting group and replace by one or more, each substituting group be independently selected from halogen, alkyl, heterocyclic radical, heteroaryl, aryl, cycloalkyl, cyano group, alkoxyl group and-S (alkyl).Suitably the limiting examples of thiazolinyl comprise vinyl, propenyl, just-butenyl, 3-methyl but-2-ene base, just-pentenyl, octenyl and decene base.

" alkylidene group " expression is by removing a difunctionality group that hydrogen atom obtained from defined alkyl above.The limiting examples of alkylidene group comprises methylene radical, ethylidene and propylidene.

" alkynyl " expression contains the aliphatic hydrocarbyl of at least one carbon-to-carbon three key, and it can be straight or branched, and comprise about 2 to about 15 carbon atoms in this chain.Preferred alkynyl have about 2 to about 12 carbon atoms in this chain; And be more preferably about 2 to about 4 carbon atoms in this chain.Side chain is represented one or more low alkyl groups, and for example methyl, ethyl or propyl group are connected to linear alkynyl chain." low-grade alkynyl " expression about 2 to about 6 carbon atoms in this chain, it can be straight or branched.Suitably the limiting examples of alkynyl comprises ethynyl, proyl, 2-butyne base and 3-methyl butynyl." alkynyl " can not be substituted, or optional can be identical or different substituting group and replace by one or more, and each substituting group is independently selected from alkyl, aryl and cycloalkyl.

" aryl " expression aromatic monocyclic shape or polycyclic loop systems comprise about 6 to about 14 carbon atoms, and preferably about 6 to about 10 carbon atoms.Aryl can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all as defined herein.Suitably the limiting examples of aryl comprises phenyl and naphthyl.

" heteroaryl " expression aromatic monocyclic shape or polycyclic loop systems comprise about 5 to about 14 annular atomses, and preferably about 5 to about 10 annular atomses, and wherein one or more annular atomses are the element beyond the carbon, and for example nitrogen, oxygen or sulphur are used separately or also.Preferred heteroaryl contains has an appointment 5 to about 6 annular atomses." heteroaryl " can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all as defined herein.Prefix azepine, oxa-or thia before the heteroaryl radical title represent that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.The nitrogen-atoms of heteroaryl can be chosen wantonly and be oxidized to its corresponding N-oxide compound." heteroaryl " also can comprise the heteroaryl of definition as mentioned that defines aryl as mentioned through being fused to.Suitably the limiting examples of heteroaryl comprises pyridyl, pyrazinyl, furyl, thienyl, pyrimidyl, pyridone (comprising the pyridone that N-replaces) isoxazolyl, isothiazolyl oxazolyl, thiazolyl, pyrazolyl, the furazan base, pyrryl, pyrazolyl, triazolyl, 1,2, the 4-thiadiazolyl group, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, the oxindole base, imidazo [1,2-a] pyridyl, imidazo [2,1-b] thiazolyl, benzo furazan base, indyl, azaindolyl, benzimidazolyl-, benzothienyl, quinolyl, imidazolyl, the thienopyridine base, quinazolyl, the Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinolyl, the benzo-aza indyl, 1,2, the 4-triazinyl, benzothiazolyl etc." heteroaryl " speech also finger divides saturated heteroaryl moieties group, for example tetrahydro isoquinolyl, tetrahydric quinoline group etc.

" aralkyl " or " arylalkyl " expression aryl-alkyl-group, wherein aryl and alkyl are all as mentioned before.Preferred aralkyl comprises low alkyl group.Suitably the limiting examples of aralkyl comprises benzyl, 2-styroyl and naphthyl methyl.Being connected with the key of parent fraction group is to pass through alkyl.

" alkylaryl " expression alkyl-aryl-group, wherein alkyl and aryl are all as mentioned before.Preferred alkylaryl comprises low alkyl group.Suitably the limiting examples of alkylaryl is a tolyl.Being connected with the key of parent fraction group is to pass through aryl.

The non-aromatics list of " cycloalkyl " expression-or the polycyclic loop systems, comprise about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms.Preferred cycloalkyl ring contains has an appointment 5 to about 7 annular atomses.Cycloalkyl can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all definition as mentioned.Suitably the limiting examples of monocycle shape cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc.Suitably the limiting examples of polycyclic cycloalkyl comprises 1-decahydro naphthyl, norcamphyl, adamantyl etc.

" cycloalkylalkyl " expression is the cycloalkyl moiety group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of cycloalkylalkyl comprises cyclohexyl methyl, adamantyl methyl etc.

" cycloalkenyl group " non-aromatics list of expression or polycyclic loop systems comprise about 3 to about 10 carbon atoms, and preferably about 5 to about 10 carbon atoms, and it contains at least one carbon-to-carbon double bond.Preferred cyclenes basic ring contains about 5 to about 7 annular atomses.Cycloalkenyl group can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all definition as mentioned.Suitably the limiting examples of monocycle shape cycloalkenyl group comprises cyclopentenyl, cyclohexenyl, ring heptan-butadienyl etc.Suitably the limiting examples of polycyclic cycloalkenyl group is a norbornene.

" cycloalkenyl alkyl " expression is the cycloalkenyl group part group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of cycloalkenyl alkyl comprises cyclopentenyl methyl, cyclohexenyl methyl etc.

" halogen " expression fluorine, chlorine, bromine or iodine.Preferably fluorine, chlorine and bromine.

" loop systems substituting group " expression is connected to the substituting group of aromatics or non-aromatics loop systems, and it is the available hydrogen in the D-loop system for example.The loop systems substituting group can be identical or different, respectively is independently selected from alkyl; thiazolinyl; alkynyl; aryl; heteroaryl; aralkyl; alkylaryl; heteroaralkyl; the impure aromatic ene base; the heteroaryl alkynyl; miscellaneous alkyl aryl; hydroxyl; hydroxyalkyl; alkoxyl group; aryloxy; aralkoxy; acyl group; aroyl; halogen; nitro; cyano group; carboxyl; carbalkoxy; aryloxycarbonyl; aromatic alkoxy carbonyl; alkyl sulphonyl; aryl sulfonyl; heteroarylsulfonyl; alkylthio; artyl sulfo; the heteroaryl sulfenyl; aromatic alkylthio; the heteroaralkyl sulfenyl; cycloalkyl; heterocyclic radical;-C (=N-CN)-NH ₂,-C (=NH)-NH ₂,-C (=NH)-NH (alkyl), Y ₁Y ₂N-, Y ₁Y ₂The N-alkyl-, Y ₁Y ₂NC (O)-, Y ₁Y ₂NSO ₂-and-SO ₂NY ₁Y ₂, Y wherein ₁With Y ₂Can be identical or differently, and be independently selected from hydrogen, alkyl, aryl, cycloalkyl and aralkyl." loop systems substituting group " also can represent single part group, and it on two adjacent carbonss of loop systems, replaces two available hydrogens (H on each carbon) simultaneously.This kind part examples of groups be methylene-dioxy, ethylenedioxy ,-C (CH ₃) ₂-etc., it forms for example with the lower section group:

" heteroaralkyl " expression is the heteroaryl moieties group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of heteroaryl comprises 2-pyridylmethyl, quinolyl methyl etc.

" heterocyclic radical " non-aromatics saturated mono ring-type of expression or polycyclic loop systems, comprise about 3 to about 10 annular atomses, preferably about 5 to about 10 annular atomses, and wherein the one or more atoms in this loop systems are the element beyond the carbon, for example nitrogen, oxygen or sulphur are used separately or also.There are not adjacent oxygen and/or sulphur atom to be present in this loop systems.Preferred heterocyclic radical contains has an appointment 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before heterocyclic radical radical title represent that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.Any-NH in the heterocyclic ring can protected precedent as-N (Boc) ,-N (CBz) ,-N (Tos) etc. and existing; This kind protection also is regarded as a part of the present invention.Heterocyclic radical can be chosen wantonly by one or more " loop systems substituting group " and replace, and it can be identical or different, and all as defined herein.The nitrogen of heterocyclic radical or sulphur atom can be chosen wantonly and be oxidized to its corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.Suitably the limiting examples of monocyclic heterocycle basic ring comprises piperidyl, pyrrolidyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidyl, 1,4-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, lactan, lactone etc." heterocyclic radical " also can represent single part group (for example carbonyl), and it is two available hydrogens on the identical carbon atoms of D-loop system simultaneously.This kind part examples of groups is a pyrrolidone:

" heterocyclic radical alkyl " expression is the heterocyclic radical part group of definition as mentioned, is linked to the parent core by moieties group (above definition).Suitably the limiting examples of heterocyclic radical alkyl comprises piperidino methyl, piperazinyl methyl etc.

" heterocycloalkenyl " expression non-aromatic monocyclic shape or polycyclic loop systems, comprise about 3 to about 10 annular atomses, preferably about 5 to about 10 annular atomses, wherein the one or more atoms in this loop systems are the element beyond the carbon, for example nitrogen, oxygen or sulphur atom, separately or and usefulness, and it contains at least one carbon-to-carbon double bond or the two keys of carbon-nitrogen.There are not adjacent oxygen and/or sulphur atom to be present in this loop systems.Preferred heterocycloalkenyl ring contains has an appointment 5 to about 6 annular atomses.Prefix azepine, oxa-or thia before heterocycloalkenyl radical title represent that at least one nitrogen, oxygen or sulphur atom exist as annular atoms respectively.Heterocycloalkenyl can be chosen wantonly by one or more loop systems substituting groups and replace, and wherein " loop systems substituting group " defines as mentioned.The nitrogen of heterocycloalkenyl or sulphur atom can be chosen wantonly and be oxidized to its corresponding N-oxide compound, S-oxide compound or S, the S-dioxide.Suitably the limiting examples of heterocycloalkenyl comprises 1,2,3,4-tetrahydro pyridyl, 1,2-dihydropyridine base, 1,4-dihydropyridine base, 1,2,3,6-tetrahydro pyridyl, 1,4,5,6-tetrahydro-pyrimidine base, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, glyoxalidine base, dihydro-oxazole base, Er Qing oxadiazole base, dihydro-thiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuran base, fluorine dihydrofuran base, 7-oxabicyclo be [2.2.1] heptenyl, dihydro-thiophene base, dihydrogen phosphorothioate pyranyl etc. also." heterocycloalkenyl " also can represent single part group (for example carbonyl), and it is two available hydrogens on the identical carbon atoms of D-loop system simultaneously.This kind part examples of groups is a pyrrolidone:

" heterocycloalkenyl alkyl " expression is the heterocycloalkenyl part group of definition as mentioned, is linked to the parent core by moieties group (above definition).

It should be noted, contain in the heteroatomic loop systems do not have hydroxyl on the carbon atom of contiguous N, O or S, and do not have N or S group on contiguous another heteroatomic carbon in the present invention.Therefore, for example in following ring:

Do not have-OH is connected directly to and is denoted as 2 and 5 carbon.

Also it should be noted, tautomeric form, for example with the lower section group:

In certain embodiments of the invention, be considered to equate.

" alkynyl alkyl " expression alkynyl-alkyl-group, wherein alkynyl and alkyl are all as mentioned before.Preferred alkynyl alkyl contains low-grade alkynyl and low alkyl group.Being connected with the key of parent fraction group is to pass through alkyl.Suitably the limiting examples of alkynyl alkyl comprises the propargyl methyl.

" heteroaralkyl " expression heteroaryl-alkyl-group, wherein heteroaryl and alkyl are all as mentioned before.Preferred heteroaralkyl contains low alkyl group.Suitably the limiting examples of aralkyl comprises pyridylmethyl and quinoline-3-ylmethyl.Being connected with the key of parent fraction group is to pass through alkyl.

" hydroxyalkyl " expression HO-alkyl-group, wherein alkyl such as preamble define.Preferred hydroxyalkyl contains low alkyl group.Suitably the limiting examples of hydroxyalkyl comprises methylol and 2-hydroxyethyl.

" acyl group " expression H-C (O)-, alkyl-C (O)-or cycloalkyl-C (O)-group, wherein various groups are all as mentioned before.Being connected with the key of parent fraction group is to pass through carbonyl.Preferred acyl group contains low alkyl group.Suitably the limiting examples of acyl group comprises formyl radical, ethanoyl and propionyl.

" aroyl " expression aryl-C (O)-group, wherein aryl as mentioned before.Being connected with the key of parent fraction group is to pass through carbonyl.Suitably the limiting examples of group comprises benzoyl and 1-naphthoyl.

" alkoxyl group " expression alkyl-O-group, wherein alkyl as mentioned before.Suitably the limiting examples of alkoxyl group comprise methoxyl group, oxyethyl group, just-propoxy-, isopropoxy and just-butoxy.Being connected with the key of parent fraction group is by ether oxygen.

" aryloxy " expression aryl-O-group, wherein aryl as mentioned before.Suitably the limiting examples of aryloxy comprises phenoxy group and naphthyloxy.Being connected with the key of parent fraction group is by ether oxygen.

" aralkoxy " expression aralkyl-O-group, wherein aralkyl as mentioned before.Suitably the limiting examples of aralkoxy comprises benzyloxy and 1-or 2-naphthalene methoxyl group.Being connected with the key of parent fraction group is by ether oxygen.

" alkylthio " expression alkyl-S-group, wherein alkyl as mentioned before.Suitably the limiting examples of alkylthio comprises methylthio group and ethylmercapto group.Being connected with the key of parent fraction group is to pass through sulphur.

" artyl sulfo " expression aryl-S-group, wherein aryl as mentioned before.Suitably the limiting examples of artyl sulfo comprises thiophenyl and naphthyl sulfenyl.Being connected with the key of parent fraction group is to pass through sulphur.

" aromatic alkylthio " expression aralkyl-S-group, wherein aralkyl as mentioned before.Suitably the limiting examples of aromatic alkylthio is a benzylthio-.Being connected with the key of parent fraction group is to pass through sulphur.

" carbalkoxy " expression alkyl-O-CO-group.Suitably the limiting examples of carbalkoxy comprises methoxycarbonyl and ethoxycarbonyl.Being connected with the key of parent fraction group is to pass through carbonyl.

" aryloxycarbonyl " expression aryl-O-C (O)-group.Suitably the limiting examples of aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.Being connected with the key of parent fraction group is to pass through carbonyl.

" aromatic alkoxy carbonyl " expression aralkyl-O-C (O)-group.Suitably the limiting examples of aromatic alkoxy carbonyl is a carbobenzoxy-(Cbz).Being connected with the key of parent fraction group is to pass through carbonyl.

" alkyl sulphonyl " expression alkyl-S (O ₂)-group.Preferred group is the low alkyl group person for alkyl wherein.Being connected with the key of parent fraction group is to pass through alkylsulfonyl.

" aryl sulfonyl " expression aryl-S (O ₂)-group.Being connected with the key of parent fraction group is to pass through alkylsulfonyl.

" be substituted " vocabulary and be shown in one or more hydrogen on the specified atom and be selected from indicated group and replace, its condition is, can not surpass specified atom at the normal valence link that exists under the situation, and this replaces and can produce stable compound.The combination of substituting group and/or variable only can produce under the stable compound in this kind combination and just can allow.So-called " stable compound " or " rock steady structure " is meant that compound is enough strong and retaining from reaction mixture, is separated to useful purity, and is deployed into effective therapeutical agent.

" optional being substituted " vocabulary shows with special groups, atomic group or the optional of part group to be selected generation.

About " purifying ", " being purified form " or " be and separate and purified form " term of compound, be meant that this compound is in the physical condition after synthetic method (for example reaction mixture) or natural origin or its combination separation.Therefore, " purifying ", " being purified form " or " being the isolation and purification form " term about compound, be meant this compound derive from purification process described herein or well known to a person skilled in the art method (for example chromatography, recrystallization etc.) after physical condition, it has enough purity, can be by described or well known to a person skilled in the art the standard analytical techniques characterized herein.

Also it should be noted that in the context of this article, scheme, embodiment and form, any carbon and heteroatoms that has less than the full price key is assumed that the hydrogen atom with enough numbers, to satisfy this valence link.

When the functional group in the compound was called as " protection ", this represented that this group is modified form, with when the compound acceptable response, get rid of this protection the position do not want side reaction.The due care base will be by those skilled in the art and reference standard textbook and is understood, T.W.Greene et al for example, Protective Groups in organic Synthesis (1991), Wiley, New York.

As any parameter (for example aryl, heterocycle, R ²Deng) when occurring surpassing one time in any composition or formula I-VI, its definition and its definition in each other existence place in each existence place is irrelevant.

" composition " speech of Shi Yonging in this article is intended to contain and a kind ofly comprises the product of specific composition with specified quantitative, and directly or indirectly makes up formed spawn by specific composition with specified quantitative.

The prodrug of The compounds of this invention and solvate also are intended to be included in this paper.The discussion of prodrug is provided in T.Higuchi and V.Stella, 14 of Pro-drugs as Novel Delivery Systems (1987) A.C.S. analects series, and at Bioreversible Carriers in DrugDesign, (1987) Edward B.Roche writes, American Medical Association and Pergamon press." prodrug " vocabulary shows and can in vivo change and the compound (for example prodrug) of pharmacologically acceptable salts, hydrate or the solvate of production (I) compound or this compound.This transformation can take place by various mechanism (for example by metabolism or chemical process), for example process hydrolytic action in blood.The discussion of prodrug purposes, by T.Higuchi and W.Stella, " Pro-drugs as NovelDelivery Systems ", A.C.S. the 14th of analects series the roll up, and at BioreversibleCarriers in Drug Design, Edward B.Roche writes, and American Medical Association and Pergamon press provide in 1987.

For example, if pharmacologically acceptable salts, hydrate or the solvate of formula (I) compound or this compound contain the carboxylic-acid functional base, then prodrug can comprise that by with the formed ester of a kind of hydrogen atom of this acidic group of group displacement, this group is (C for example ₁-C ₈) alkyl, (C ₂-C ₁₂) alkanoyloxymethyl, 1-(alkanoyloxy) ethyl with 4 to 9 carbon atoms, 1-methyl isophthalic acid-(alkanoyloxy)-ethyl with 5 to 10 carbon atoms, alkoxy carbonyl yloxy ylmethyl with 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy) ethyl with 4 to 7 carbon atoms, 1-methyl isophthalic acid-(alkoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, N-(carbalkoxy) amino methyl with 3 to 9 carbon atoms, 1-(N-(carbalkoxy) amino) ethyl with 4 to 10 carbon atoms, the 3-phthalidyl, 4-crotons lactone group, gamma-butyrolactone-4-base,-N, N-(C ₁-C ₂) alkylamino (C ₂-C ₃) alkyl (for example β-dimethylaminoethyl), carbamyl-(C ₁-C ₂) alkyl, N, N-two (C ₁-C ₂) alkylcarbamoyl group-(C ₁-C ₂) alkyl, and piperidyl-, tetramethyleneimine is at-or morpholinyl (C ₂-C ₃) alkyl etc.

Similarly, if formula (I) compound contains alcohol functional group, then prodrug can form by the hydrogen atom with a kind of this alcohol radical of group displacement, and this group is (C for example ₁-C ₆) alkanoyloxymethyl, 1-((C ₁-C ₆) alkanoyloxy) ethyl, 1-methyl isophthalic acid-((C ₁-C ₆) alkanoyloxy) ethyl, (C ₁-C ₆) alkoxy carbonyl yloxy ylmethyl, N-(C ₁-C ₆) alkoxycarbonyl ammonia ylmethyl, succinyl, (C ₁-C ₆) alkyloyl, alpha-amino group (C ₁-C ₄) alkyl, aryl-acyl and α-aminoacyl or α-aminoacyl-α-aminoacyl, wherein each α-aminoacyl independently be selected from natural generation L-amino acids, P (O) (OH) ₂,-P (O) (O (C ₁-C ₆) alkyl) ₂Or glycosyl (owing to removing the formed group of hydroxyl of carbohydrate hemiacetal form) etc.

If formula (I) compound incorporates the amine functional group into, then prodrug can be by forming with the hydrogen atom in this amine groups of a kind of group displacement, and this group is R-carbonyl, RO-carbonyl, NRR '-carbonyl for example, wherein R and R ' each independently be (C ₁-C ₁₀) alkyl, (C ₃-C ₇) cycloalkyl, benzyl, or the R-carbonyl be natural α-aminoacyl or natural α-aminoacyl ,-C (OH) C (O) OY ¹, Y wherein ¹Be H, (C ₁-C ₆) alkyl or benzyl ,-C (Oy ²) Y ³, Y wherein ²Be (C ₁-C ₄) alkyl, and Y ³Be (C ₁-C ₆) alkyl, carboxyl (C ₁-C ₆) alkyl, amino (C ₁-C ₄) alkyl or list-N-or two-N, N-(C ₁-C ₆) alkyl amino alkyl ,-C (Y ⁴) Y ⁵, Y wherein ⁴Be H or methyl, and Y ⁵Be list-N-or two-N, N-(C ₁-C ₆) alkylamino morpholinyl, piperidines-1-base or tetramethyleneimine-1-base etc.

One or more The compounds of this invention not solvent chemical combination form exist, and exist with solvent chemical combination form, have pharmacy acceptable solvent for example water, ethanol etc., and this invention is intended to comprise solvent chemical combination and solvent chemical combination form not.The physics association of " solvate " expression The compounds of this invention and one or more solvent molecules.This physics association relates to ionic and covalent bonding in various degree, comprises hydrogen bond.In some cases, solvate can separate, for example, and when one or more solvent molecules are impregnated in the lattice of crystalline solid." solvate " contains solution and separable solvate.The limiting examples of appropriate solvent compound comprises ethanol compound, methyl alcohol compound etc." hydrate " is solvate, and wherein solvent molecule is H ₂O.

One or more The compounds of this invention can be chosen wantonly and be converted to solvate.The preparation of solvate generally is known.Therefore, for example, M.Caira et al, J.Pharmaceutical Sci., 93 (3), 601-611 (2004) describes the anti-mycotic agent fluconazole and prepare solvate in ethyl acetate and from water.The similar preparation of solvate, half solvate, hydrate etc., by E.C.vanTonder et al, AAPS PharmSciTech., 5 (1), paper 12 (2004); And A.L.Bingham et al, Chem.Commun., 603-604 (2001) describes.The unrestricted method of a kind of typical case relates in the required solvent (organic or water or its mixture) that makes The compounds of this invention be dissolved in aequum under being higher than envrionment temperature, and solution is cooled off being enough to form under the crystalline speed, separates by standard method then.Analytical technology, for example I.R. spectroscopy shows that solvent (or water) is present in the crystallization as solvate (or hydrate).

" significant quantity " or " treatment significant quantity " is intended to describe The compounds of this invention or composition effectively suppresses the above amount of indication disease, and therefore produces needed treatment, improvement, inhibition or prophylactic effect.

Formula I-VI compound can form salt, and it also within the scope of the invention.This paper is to the denotion of formula I-VI compound, and what should understand is, unless point out in addition, otherwise comprise and censure its salt.When adopting in this article, " salt " vocabulary shows the acid-salt that forms with inorganic and/or organic acid, and the basic salt that forms with inorganic and/or organic bases.In addition, when formula I-VI compound contains the basic moiety group such as but not limited to pyridine or imidazoles, and the acidic moiety group such as but not limited to carboxylic acid both the time, then can form zwitter-ion (" inner salt "), and be included in as used in this article in " salt " speech.The salt of pharmacy acceptable (meaning is can accept on nontoxicity, the physiology) is for preferred, although other salt also can use.The salt of formula I-VI compound can be for example by making formula I-VI compound and certain a certain amount of acid or alkali, and equivalent for example can be deposited in wherein those media or reacts in aqueous medium at for example salt, then lyophilize and forming.

Acid salt for example comprises acetate, ascorbate salt, benzoate, benzene sulfonate, hydrosulphate, borate, butyrates, Citrate trianion, camphorate, camsilate, fumarate, hydrochloride, hydrobromate, hydriodate, lactic acid salt, maleic acid salt, methane sulfonates, naphthalenesulfonate, nitrate, oxalate, phosphoric acid salt, propionic salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate (toluenesulfonate) (also being called tosylate (tosylate)) etc.In addition, it is generally acknowledged and be applicable to the acids that pharmaceutically can use salt from alkaline pharmaceutical compound formation, be for example by P.Stahlet al, Camille G. (eds.) Handbook of Pharmaceutical Salts.Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S.Berge et al, Journal ofPharmaceutical Sciences (1977) 66 (1)1-19; P.Gould, International J.ofPharmaceutics (1986) 33201-217; Anderson et al, The Practice ofMedicinal Chemistry (1996), Academic Press, New York; And at TheOrange Book (Food﹠amp; Drug Admini stration, Washington, D.C. is on its website) discussed.It is for reference that this type of disclosure is incorporated this paper into.

Basic salt for example, comprise ammonium salt, an alkali metal salt, for example sodium, lithium and sylvite, alkaline earth salt, for example calcium and magnesium salts, and the salt of organic bases (for example organic amine), this bases is dicyclohexyl amine, tertiary butyl amine for example, and and amino acid whose salt, this amino acid is arginine, Methionin etc. for example.The alkalescence nitrogen-containing group can be quaternized with reagent, and this reagent is elementary alkyl halide (for example muriate of methyl, ethyl and butyl, bromide and iodide), sulfuric acid dialkyl (for example sulfuric ester of dimethyl, diethyl and dibutyl), long-chain halogenide (for example muriate of decyl, lauryl and stearyl, bromide and iodide), aralkyl halide (for example benzyl and styroyl bromination thing) and other for example.

All these type of hydrochlorates and alkali salt are intended to be the pharmacologically acceptable salts in the scope of the invention, and for the purposes of this invention, all acid and alkali salt are considered to be equivalent to the free form of respective compound.

The pharmacy acceptable esters of The compounds of this invention comprises following group: (1) is by the carboxylic acid esters that esterification obtained of hydroxyl; wherein the non-carbonyl moiety group of ester group group's carboxylic moiety be selected from the straight or branched alkyl (for example ethanoyl, just-propyl group, the tertiary butyl or normal-butyl), alkoxyalkyl (for example methoxymethyl), aralkyl (for example benzyl), aryloxy alkyl (for example phenoxymethyl), aryl (for example; phenyl, it is optional by for example halogen, C _1-4Alkyl or C _1-4Alkoxyl group or amino replacement the); (2) sulfonic acid esters, for example alkyl-or aralkyl alkylsulfonyl (for example methane sulfonyl); (3) amino acid esters (for example different valerian aminoacyl of L-or L-isoleucyl base); (4) phosphonic acid ester, and (5) single-, two-or triguaiacyl phosphate class.Phosphoric acid ester can be further by for example C _1-20Alcohol or its reactive derivatives, or by 2,3-two (C _6-24) the acylglycerol esterification.

Formula I-VI compound, with and salt, solvate, ester and prodrug, can its tautomeric form have (for example as acid amides or imido ether).All this kind tautomeric forms are intended to covered in herein, as a part of the present invention.

Formula (I) compound can contain asymmetric or chiral centre, therefore exists with different stereoisomeric forms in any ratio.Desirablely be, all stereoisomeric forms in any ratio of formula (I) compound with and composition thereof comprise that racemic mixture constitutes a part of the present invention.In addition, the present invention includes all geometry and positional isomerss.For example, if formula (I) compound is incorporated two keys or fused rings into, cis-within the scope of the invention involved then with trans-form and mixture.

The diastereo-isomerism mixture can its physical chemistry difference be the basis, by well known to a person skilled in the art method, for example by chromatography and/or fractional crystallization, is separated into its each diastereomer.Enantiomer can be separated by making enantiomeric mixture change into non-enantiomer mixture, its mode is and suitable optically active compound (chiral adjuvant for example, for example chiral alcohol or MosherShi chlorine acyl) reaction, separate diastereomer, make each diastereomer transform (for example hydrolysis) again and become its corresponding pure enantiomer.Some formulas (I) compound also can be atropisomer (for example biaryl base class of Qu Daiing), and is considered to a part of the present invention.Enantiomer also can utilize chirality HPLC post to separate.

Formula (I) compound can also different tautomeric forms exist, and all these type of forms are within the scope of the invention involved.For example, all keto-enols of compound and imines-enamine form, also in the present invention involved.

The compounds of this invention (salt, solvate, ester and the prodrug that comprise this compound, and the salt of this prodrug, solvate and ester) all steric isomers (for example geometrical isomer, optical isomer etc.), for example can owing to exist due to the asymmetric carbon on the different substituents those, comprise enantiomerism form (itself even can exist in the presence of not), rotational isomeric form, atropisomer and diastereomeric form at asymmetric carbon, be intended to covered in the scope of the present invention, for example positional isomers (for example 4-pyridyl and 3-pyridyl).(for example, if formula (I) compound is incorporated two keys or fused rings into, cis-within the scope of the invention involved then with trans-form and mixture.For example, all keto-enols of this compound and imines-enamine form, also in the present invention involved).Each steric isomer of The compounds of this invention can for example be substantially free of other isomer, or can be for example through being mixed into racemoid, or with all other or other steric isomer through selecting mixes.Chiral centre of the present invention can have as advising defined S or R configurations by IUPAC 1974.The use of term " salt ", " solvate ", " ester ", " prodrug " etc. is intended to similarly be applicable to salt, solvate, ester and the prodrug of enantiomer, steric isomer, rotational isomer, tautomer, positional isomers, racemoid or the prodrug of The compounds of this invention.

The present invention also comprises the The compounds of this invention that identifies in the isotropic substance mode, it is with described herein those are identical, but except the following situation, promptly one or more atoms are had by one that atomic mass or total mass number are different from usually the atomic mass found on natural or the atom of total mass number is replaced.Can be merged in isotropic substance example in the The compounds of this invention comprises and for example is respectively the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.

Some formula that identifies in the isotropic substance mode (I) compound (for example with ³H with ¹⁴The C sign) can be used in compound and/or the detection of substrate tissue distribution.(meaning promptly in tritiate ³H) and carbon-14 (meaning promptly ¹⁴C) isotropic substance is particularly preferred, because of it is easy to preparation and detectability.In addition, with than the heavy isotropic substance for example deuterium (meaning promptly ²H) replace, can provide because some that higher metabolic stability caused treated interests (for example, increasing in vivo half life or reduction dosage requirement), therefore in some cases may be preferred.Generally can make according to disclosed program in similar hereinafter scheme and/or the example with formula (I) compound that the isotropic substance mode identifies, its mode is to replace the reagent that does not identify in the isotropic substance mode with the reagent that suitable isotropic substance mode identifies.

The polycrystalline form of formula I-VI compound, and the polycrystalline form of the salt of formula I compound, solvate, ester class and prodrug will comprise in the present invention.

Following abbreviation is used hereinafter, and has following implication:

Boc is a tert-butoxycarbonyl, and dba is a diphenylmethylene acetone, and DMF is N, dinethylformamide, DMSO are dimethyl sulfoxide (DMSO), and EtOAc is an ethyl acetate, LCMS is a liquid chromatography-mass spectrometry, and MeOH is a methyl alcohol, and NMR is a nucleus magnetic resonance, PBS is a phosphate buffered saline (PBS), SPA is a scintillation proximity assay, and Tf is trifluoromethane sulfonic acid ester/salt, and TFA is that trifluoroacetic acid and Xantphos are 9,9-dimethyl-4, two (diphenylphosphine) Xanthenes of 5-.Me4Si is the tetramethyl-silicomethane, and DIEA is a diisopropylethylamine, and SGC is a silicagel column; TMSCHN2 is the trimethyl silyl diazomethane, and BBr3 is the tribromo borine, and m-CPBA is a metachloroperbenzoic acid; CDI is a N,N'-carbonyldiimidazole, and HATU is a 2-(1H-azepine benzo triazol-1-yl-1,13; 3-tetramethyl-urea hexafluorophosphate; NaH is a sodium hydride, and SiO2 is a silicon-dioxide, and CBZ is the benzyloxy carbonyl; Tos is a p-toluenesulfonyl, and CH3CN is an acetonitrile.

Heterocyclic amide of the present invention

The invention provides formula I compound:

Formula I

Or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer; Wherein encircle A, M, X, Y, Z, T, R ¹, R ²And R ³As mentioned at the definition of formula (I).

In one embodiment, in formula I, the substituting group-NR of ring A except showing ²C (=T)-(ring that comprises M, X, Y and Z) and R ³Also can choose wantonly in addition and have described 5-to 6-unit aryl, heterocyclic radical, heterocycloalkenyl or heteroaryl ring, optionally be selected from following substituting group and replace by one or more: halogen, cyano group, hydroxyl, alkoxyl group, aryloxy, alkyl ,-NR ⁴R ⁵, haloalkyl, halogenated alkoxy, nitro, aryl ,-C (=O) R ⁴,-C (=O) OR ⁴,-C (=O) NR ⁴R ⁵,-OC (=O) R ⁴With-NR ⁴C (=O) R ⁴

In another embodiment, in formula I, each R ¹Aryl, heterocyclic radical, heterocycloalkenyl and heteroaryl, and-C (=O) N (R ⁴) aryl ,-C (=O) N (R ⁴) heteroaryl ,-C (=O) N (R ⁴) heterocyclic radical ,-C (=O) N (R ⁴) heterocycloalkenyl ,-N (R ⁴) C (=O) aryl ,-N (R ⁴) C (=O) heteroaryl ,-N (R ⁴) C (=O) heterocyclic radical and-N (R ⁴) C (=O) heterocycloalkenyl should " heterocyclic radical ", " heterocycloalkenyl ", " aryl " and " heteroaryl " part is optional has described 5-to 6-unit cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical, heterocycloalkenyl or a heteroaryl ring, optionally is selected from following substituting group replacement by one or more: halogen, hydroxyl, alkoxyl group, aryloxy, alkyl ,-NR ⁴R ⁵, haloalkyl, halogenated alkoxy, nitro, aryl, heteroaryl ,-C (=O) R ⁴,-C (=O) OR ⁴,-C (=O) NR ⁴R ⁵,-OC (=O) R ⁴,-NR ⁴C (=O) R ⁴,-O-alkyl-O-alkyl ,-O-alkyl-O-alkyl-O-alkyl ,-O-alkyl-heterocyclic radical ,-S-R ⁴, heterocyclic radical and-S (=O) ₂-R ⁴

In another embodiment, in formula I, X, Y and Z are C (R).

In another embodiment, in formula I, T is O.

In another embodiment, in formula I, ring A is a heteroaryl.

In another embodiment, in formula I, ring A is a pyridyl.

In another embodiment, in formula I, R is H.

In another embodiment, in formula I, R ²Be H.

In another embodiment again, in formula I, R ³It is heterocyclic radical.

In another embodiment, formula I compound is expressed as with Formula Il

Formula II

Or its pharmacologically acceptable salts, solvate, ester or prodrug, wherein:

Z ¹Be CH or N;

Z ²Be CH ₂Or NH

R ⁶And R ⁷Be independently selected from H, heteroaryl ,-C (=O) aryl and-C (=O) heteroaryl, and, perhaps R ⁶And R ⁷With showing that the nitrogen-atoms that is connected with them is a heterocyclic radical, wherein when described heterocyclic radical had two substituting groups on adjacent carbons, the carbon atom that described substituting group connects with them formed 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ⁸Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

N is 0,1 or 2.

In another embodiment, in formula II, optional have described 5-to 6-unit heterocyclic radical, aryl or heteroaryl-NR ⁶R ⁷Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group ,-O-alkyl-O-alkyl ,-O-alkyl-O-alkyl-O-alkyl ,-O-alkyl-heterocyclic radical ,-S-alkyl, heterocyclic radical ,-C (=O) OH ,-C (=O) the O alkyl ,-S (=O) ₂-heterocyclic radical, halogen and alkyl.

In another embodiment, in formula II, Z ¹Be N.

In another embodiment, in formula II, Z ¹Be CH.

In another embodiment, in formula II, Z ²Be CH ₂

In another embodiment, in formula II, Z ²Be NH.

In another embodiment, in formula II, Z ¹Be N, and Z ²Be NH.

In another embodiment, in formula II, Z ¹Be N and Z ²Be CH ₂

In further embodiment, in formula II, Z ¹Be CH and Z ²Be CH ₂

In another embodiment, in formula II, Z ¹Be N, Z ²Be NH, and n is 0.

In another embodiment, in formula II, Z ¹Be N and Z ²Be CH ₂, and n is 1.

In another embodiment, in formula II, Z ¹Be CH and Z ²Be CH ₂, and n is 1.

In another embodiment, in formula II, R ⁸Be-NH ₂

In another embodiment, in formula II, Z ¹Be N and Z ²Be CH ₂, n is 1, and R ⁸Be-NH ₂

In another embodiment, in formula II, Z ¹Be CH and Z ²Be CH ₂, and n is 1, and R ⁸Be-NH ₂

In another embodiment, in formula II ,-NR ⁶R ⁷It is-NHC (=O) aryl.

In another embodiment, in formula II ,-NR ⁶R ⁷Be-NHC (=O) aryl, wherein said-NHC (=O) aryl should " aryl " optional is selected from following substituting group by one or more and replaces: alkyl, alkoxyl group, halogenated alkoxy, haloalkyl and halogen.

In another embodiment, in formula II, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁶R ⁷Heterocyclic radical is optional and benzene or pyridine ring condensed heterocycle base.

In another embodiment, in formula II ,-NR ⁶R ⁷Be-NH (2-pyrazinyl).

In another embodiment, in formula II ,-NR ⁶R ⁷Be selected from:

They each is optional substituted.

In another embodiment, in formula II, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁶R ⁷Heterocyclic radical is optional and benzene or pyridine ring condensed heterocycle base, has wherein that described 5-to the 6-unit heterocyclic radical of described optional condensed benzene or pyridine ring is optional to be selected from following substituting group and to replace by one or more: methyl, methoxyl group, 4-piperidyl ,-C (=O) OH ,-C (=O) OCH ₃,-S (=O) ₂-pyrrolidyl, fluorine, chlorine ,-CH ₂CH ₂-(1-morpholinyl) ,-OCH ₂CH ₂-(1-morpholinyl) ,-CH ₂CH ₂-N (CH ₃) ₂With-OCH ₂CH ₂-N (CH ₃) ₂

In another embodiment, in formula II, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁶R ⁷Heterocyclic radical is optional and benzene or pyridine ring condensed heterocycle base, has wherein that described 5-to the 6-unit heterocyclic radical of described optional condensed benzene or pyridine ring is optional to be selected from following substituting group and to replace by one or more: methyl, methoxyl group, 4-piperidyl ,-C (=O) OH ,-C (=O) OCH ₃,-S (=O) ₂-pyrrolidyl, fluorine, chlorine ,-CH ₂CH ₂-(1-morpholinyl) ,-OCH ₂CH ₂-(1-morpholinyl) ,-CH ₂CH ₂-N (CH ₃) ₂,-OCH ₂CH ₂OCH ₃With-OCH ₂CH ₂-N (CH ₃) ₂

In another embodiment, formula II compound is selected from:

Or its pharmacologically acceptable salts or ester.

In another embodiment, formula I compound is expressed as with following formula IIA:

Formula IIA

Wherein:

Z ¹Be CH or N;

Z ²Be CH ₂Or NH

Each R ²Be H or alkyl independently;

R ^6aBe selected from aryl or heteroaryl;

R ⁸Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

N is 0,1 or 2.

In another embodiment, in formula II, Z ¹Be N.

In another embodiment, in formula IIA, Z ¹Be CH.

In another embodiment, in formula IIA, Z ²Be CH ₂

In another embodiment, in formula IIA, Z ²Be NH.

In another embodiment, in formula IIA, Z ¹Be N, and Z ²Be NH.

In another embodiment, in formula IIA, Z ¹Be N and Z ²Be CH ₂

In further embodiment, in formula IIA, Z ¹Be CH and Z ²Be CH ₂

In another embodiment, in formula IIA, Z ¹Be N, Z ²Be NH, and n is 0.

In another embodiment, in formula IIA, Z ¹Be N and Z ²Be CH ₂, and n is 1.

In another embodiment, in formula IIA, Z ¹Be CH and Z ²Be CH ₂, and n is 1.

In another embodiment, in formula IIA, R ^6aIt is aryl.

In another embodiment, in formula IIA, R ^6aAryl is a phenyl.

In another embodiment, in formula IIA, R ^6aPhenyl is optional to be selected from following substituting group and to replace by one or more: methoxyl group, trifluoromethyl, fluorine and chlorine.

In another embodiment, formula IIA compound is selected from:

Or its pharmacologically acceptable salts or ester.

In another embodiment, formula I compound is expressed as following formula III:

Formula III

Or its pharmacologically acceptable salts, solvate, ester or prodrug, wherein in formula III:

Z ³Be CH or N;

Z ⁴Be CH ₂Or NH;

R ⁹Be-C (=O) NH (aryl), aryl or heteroaryl, wherein said R ⁹Aryl or heteroaryl are connected with pyridine ring by carbon atom, wherein when described aryl or heteroaryl had two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ¹⁰Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

M is 0,1 or 2.

In another embodiment, in formula III, optional described R with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁹Aryl or heteroaryl are optional to be selected from following substituting group and to replace by one or more: heterocyclic radical, alkoxyl group, aryl and alkyl.

In another embodiment, in formula III, Z ¹Be N.

In another embodiment, in formula III, Z ¹Be CH.

In another embodiment, in formula III, Z ¹Be CH ₂

In another embodiment, in formula III, Z ²Be NH.

In another embodiment, in formula III, Z ¹Be N, and Z ²Be NH.

In another embodiment, in formula III, Z ¹Be N and Z ²Be CH ₂

In another embodiment, in formula III, Z ¹Be CH and Z ²Be CH ₂

In another embodiment, in formula III, Z ¹Be N, Z ²Be NH, and n is 0.

In another embodiment, in formula III, Z ¹Be N and Z ²Be CH ₂, and n is 1.

In another embodiment, in formula III, Z ¹Be CH, Z ²Be CH ₂, and n is 1.

In another embodiment, in formula III, R ⁹It is-C (=O) NH aryl.

In another embodiment, in formula III, R ⁹Be-C (=O) NH aryl, wherein-C (=O) the described aryl of NH aryl is optional is selected from following substituting group by one or more and replaces: halogen, haloalkyl, alkoxyl group, halogenated alkoxy and alkyl.

In another embodiment, in formula III, R ⁹Be aryl or heteroaryl, and be selected from: phenyl, 4-pyridyl, 2-(6-(1-piperazinyl)) pyridyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo (dihydro) furyl, 3-pyridyl, 2-thienyl, 3-thienyl, 5-pyrimidyl, benzopyrrole base, benzo morpholinyl, benzo pyridyl, phenyl, 3-pyrryl and oxazolyl, it is respectively optional naturally substituted.

In another embodiment, in formula III, R ⁹Be aryl or heteroaryl, and be selected from: phenyl, 4-pyridyl, 2-(6-(1-piperazinyl)) pyridyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo (dihydro) furyl, 3-pyridyl, 2-thienyl, 3-thienyl, 5-pyrimidyl, benzopyrrole base, benzo morpholinyl, benzo pyridyl, phenyl, 3-pyrryl are with oxazolyl, it is respectively optional naturally substituted, wherein said R ⁹Benzofuryl, benzothienyl, benzimidazolyl-, benzo (dihydro) furyl, benzopyrrole base, benzo morpholinyl and benzo pyridyl are selected from:

They each is optional substituted.

In another embodiment, in formula III, optional described R with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁹Aryl or heteroaryl are optional to be selected from following substituting group and to replace by one or more: 1-piperazinyl, methoxyl group, methyl, 1-morpholinyl ,-CH ₂-(1-morpholinyl) and phenyl.

In another embodiment, the formula III compound is selected from:

Or its pharmacologically acceptable salts, solvate, ester or prodrug.

In another embodiment, formula I compound is expressed as with following formula IV:

Formula IV

Or its pharmacologically acceptable salts or ester, wherein:

Z ⁵Be CH or N;

Z ⁶Be CH ₂Or NH;

R ¹¹And R ¹²Be H and alkyl independently, wherein said alkyl is optional to be replaced by aryl, perhaps R wherein ¹¹And R ¹²With showing that the nitrogen-atoms that is connected with them is a heterocyclic radical, wherein when described heterocyclic radical had two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ¹³Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

P is 0,1 or 2.

In another embodiment, in formula IV, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹¹R ¹²Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group, halogen, alkyl, heterocyclic radical and aryl.

In another embodiment, in formula IV, Z ⁵Be N.

In another embodiment, in formula IV, Z ⁵Be CH.

In another embodiment, in formula IV, Z ⁵Be CH ₂

In another embodiment, in formula IV, Z ⁵Be NH.

In another embodiment, in formula IV, Z ⁵Be N, and Z ⁶Be NH.

In another embodiment, in formula IV, Z ⁵Be N and Z ⁶Be CH ₂

In another embodiment, in formula IV, Z ⁵Be CH and Z ⁶Be CH ₂

In another embodiment, in formula IV, Z ⁵Be N, Z ⁶Be NH, and p is 0.

In another embodiment, in formula IV, Z ⁵Be N, Z ⁶Be CH ₂, and p is 1.

In another embodiment, in formula IV, Z ⁵Be CH, Z ⁶Be CH ₂, and p is 1.

In another embodiment, in formula IV, R ¹³Be-NH ₂

In another embodiment, in formula IV, Z ⁵Be N, Z ⁶Be CH ₂, p is 1, and R ¹³Be-NH ₂

In another embodiment, in formula IV, Z ⁵Be CH, Z ⁶Be CH ₂, p is 1, and R ¹³Be-NH ₂

In another embodiment, in formula IV, R ¹¹And R ¹²Be H and alkyl independently.

In another embodiment, in formula IV, described R ¹¹And R ¹²Alkyl is alkyl-aryl independently.

In another embodiment, in formula IV, described R ¹¹And R ¹²Alkyl is alkyl-aryl independently, and " aryl " of wherein said alkyl-aryl part is optional to be selected from following substituting group and to replace by one or more: halogen and alkoxyl group.

In another embodiment, in formula IV, R ¹¹And R ¹²Be independently selected from: H, methyl ,-CH ₂-(3-fluorophenyl) ,-CH ₂-(3-p-methoxy-phenyl) ,-CH ₂-phenyl ,-CH ₂CH ₂-phenyl ,-CH ₂CH ₂-(3-p-methoxy-phenyl) and-CH ₂CH ₂-(3-fluorophenyl).

In another embodiment, in formula IV, described-NR ¹¹R ¹²Be selected from: pyrrolidyl, piperidyl,

It is respectively optional naturally substituted.

In another embodiment, in formula IV, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁹R ¹⁰Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: methoxyl group, fluorine, chlorine ,-CH ₂CH ₂N (CH ₃) ₂,-OCH ₂CH ₂-(1-morpholinyl), 2-p-methoxy-phenyl, phenyl and 1-pyrrolidyl.

In another embodiment, formula IV compound is selected from:

Or its pharmacologically acceptable salts, solvate, ester or prodrug.

In another embodiment, formula I compound is expressed as with following formula IV (A):

Formula IV (A)

Or its pharmacologically acceptable salts or ester, wherein in formula III:

Z ³Be CH or N;

Z ⁴Be CH ₂Or NH;

R ^9aBe-N (R ²)-C (=O)-N (R ²)-aryl, aryl or heteroaryl, wherein each R ²Be H or alkyl independently, wherein said R ^9aAryl or heteroaryl are connected with pyrimidine ring by carbon atom, wherein work as at arbitrary aforementioned R ^9aWhen each in the group described " aryl " and " heteroaryl " had two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form a 5-to 6-unit heterocyclic radical, aryl or heteroaryl; Wherein when the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl had two substituting groups on adjacent carbons, described substituting group can be chosen the carbon atom that connects with them wantonly and form the 2nd 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ¹⁰Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

M is 0,1 or 2.

In another embodiment, in formula IV (A), R ^9aAryl or heteroaryl, perhaps optional described-N (R with the first heterocyclic radical of described first and second 5-to 6-, aryl or heteroaryl ²)-C (=O) N (R ²)-aryl should " aryl " part, optionally be selected from following substituting group and replace by one or more: heterocyclic radical, heteroaryl, alkoxyl group, alkyl, aryloxy, dialkyl amido, halogen ,-S (=O) ₂Alkyl ,-the S-alkyl ,-C (=O) alkyl ,-NHC (=O) alkyl ,-O-alkyl-cycloalkyl ,-C (=O) N (alkyl) ₂,-NHC (=O) NH (alkyl) and-C (=O) NH (alkyl).

In another embodiment, in formula IV (A), Z ¹Be N.

In another embodiment, in formula IV (A), Z ¹Be CH.

In another embodiment, in formula IV (A), Z ²Be CH ₂

In another embodiment, in formula IV (A), Z ²Be NH.

In another embodiment, in formula IV (A), Z ¹Be N, and Z ²Be NH.

In another embodiment, in formula IV (A), Z ¹Be N and Z ²Be CH ₂

In another embodiment, in formula IV (A), Z ¹Be CH and Z ²Be CH ₂

In another embodiment, in formula IV (A), Z ¹Be N, Z ²Be NH, and n is 0.

In another embodiment, in formula IV (A), Z ¹Be N, Z ²Be CH ₂, and n is 1.

In another embodiment, in formula IV (A), Z ¹Be CH, Z ²Be CH ₂, and n is 1.

In another embodiment, in formula IV (A), R ^9aAryl or heteroaryl, perhaps optional described-N (R with the first heterocyclic radical of described first and second 5-to 6-, aryl or heteroaryl ²)-C (=O) R ²-aryl should " aryl " part be selected from: phenyl, indyl, furyl, morpholinyl, pyridyl, indazolyl, pyrimidyl, benzofuryl, benzothienyl, benzo pyridyl, benzothiazolyl, pseudoindoyl, benzimidazolyl-, oxazolyl,

It is respectively optional naturally substituted.

In another embodiment, in formula IV (A), R ^9aAryl or heteroaryl

, perhaps optional described-N (R with the first heterocyclic radical of described first and second 5-to 6-, aryl or heteroaryl ²)-C (=O) NR ²-aryl should " aryl " part, optionally be selected from following substituting group and replace by one or more: 1-pyrrolidyl, methoxyl group, 1-morpholinyl ,-N (CH ₃) ₂, bromine, fluorine, phenoxy group ,-S (=O) ₂CH ₃,-S-CH ₃, methyl, isopropoxy ,-C (=O) OCH ₃,-NH-C (=O)-CH ₃,-O-CH ₂-cyclopropyl ,-C (=O)-N (CH ₂CH ₃) ₂,-NH-C (=O) NHCH ₂CH ₃With-C (=O) NCH ₃

In another embodiment, formula IV (A) compound is selected from:

Or its pharmacologically acceptable salts.

In another embodiment, formula I compound is expressed as with following formula V:

Formula V

Or its pharmacologically acceptable salts, solvate, ester or prodrug, wherein:

Z ⁷Be CH or N;

Z ⁸Be CH ₂Or NH;

R ¹⁴And R ¹⁵With showing that the nitrogen-atoms that is connected with them is a heterocyclic radical, wherein when described heterocyclic radical had two substituting groups on adjacent carbons, the carbon atom that described substituting group connects with them formed 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ¹⁶Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

Q is 0,1 or 2.

In another embodiment, in formula V, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹⁴R ¹⁵Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group, halogen, alkyl and aryl.

In another embodiment, in formula V, Z ⁷Be N.

In another embodiment, in formula V, Z ⁷Be CH.

In another embodiment, in formula V, Z ⁸Be CH ₂

In another embodiment, in formula V, Z ⁸Be NH.

In another embodiment, in formula V, Z ⁷Be N, and Z ⁸Be NH.

In another embodiment, in formula V, Z ⁷Be N and Z ⁸Be CH ₂

In another embodiment, in formula V, Z ⁷Be CH and Z ⁸Be CH ₂

In another embodiment, in formula V, q is 0.

In another embodiment, in formula V, Z ⁷Be N, Z ⁸Be NH, and q is 0.

In another embodiment, in formula V, q is 1.

In another embodiment, in formula V, Z ⁷Be N, Z ⁸Be CH ₂, and q is 1.

In another embodiment, in formula V, Z ⁷Be CH, Z ⁸Be CH ₂, and q is 1.

In another embodiment, in formula V, R ¹⁶Be-NH ₂

In another embodiment, in formula V, Z ⁷Be N, Z ⁸Be CH ₂, q is 1, and R ¹⁶Be-NH ₂

In another embodiment, in formula V, Z ⁷Be CH, Z ⁸Be CH ₂, q is 1, and R ¹⁶Be-NH ₂

In another embodiment, in formula V ,-NR ¹⁴R ¹⁵Be benzo-fused tetramethyleneimine, it is optional substituted.

In another embodiment, formula V compound is

Or its pharmacologically acceptable salts, solvate, ester or prodrug.

In another embodiment, formula I compound is expressed as with following formula VI:

Formula VI

Or its pharmacologically acceptable salts, solvate, ester or prodrug, wherein:

Z ⁹Be CH or N;

Z ¹⁰Be CH ₂Or NH;

R ¹⁷And R ¹⁸With showing that the nitrogen-atoms that is connected with them is a heterocyclic radical, wherein when described heterocyclic radical had two substituting groups on adjacent carbons, the carbon atom that described substituting group connects with them formed 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ¹⁹Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

R is 0,1 or 2.

In another embodiment, in formula VI, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹⁴R ¹⁵Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group, halogen, alkyl and aryl.

In another embodiment, in formula VI, Z ⁹Be N.

In another embodiment, in formula VI, Z ⁹Be CH.

In another embodiment, in formula VI, Z ¹⁰Be CH ₂

In another embodiment, in formula VI, Z ¹⁰Be NH.

In another embodiment, in formula VI, Z ⁹Be N, and Z ¹⁰Be NH.

In another embodiment, in formula VI, Z ⁹Be N and Z ¹⁰Be CH ₂

In another embodiment, in formula VI, Z ⁹Be CH and Z ¹⁰Be CH ₂

In another embodiment, in formula VI, q is 0.

In another embodiment, in formula VI, Z ⁹Be N, Z ¹⁰Be NH, and q is 0.

In another embodiment, in formula VI, q is 1.

In another embodiment, in formula VI, Z ⁹Be N, Z ¹⁰Be CH ₂, and q is 1.

In another embodiment, in formula VI, Z ⁹Be CH, Z ¹⁰Be CH ₂, and q is 1.

In another embodiment, in formula VI, R ¹⁹Be-NH ₂

In another embodiment, in formula VI, Z ⁹Be N, Z ¹⁰Be CH ₂, q is 1, and R ¹⁹Be-NH ₂

In another embodiment, in formula VI, Z ⁹Be CH, Z ¹⁰Be CH ₂, q is 1, and R ¹⁹Be-NH ₂

In another embodiment, in formula VI ,-NR ¹⁷R ¹⁸Be selected from:

It is respectively optional naturally substituted.

In another embodiment, in formula VI, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹³R ¹⁴Heterocyclic radical is optional to be replaced by one or more alkoxy substituents.

In another embodiment, in formula VI, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹³R ¹⁴Heterocyclic radical is optional to be replaced by one or more alkoxy substituents, and wherein said alkoxyl group is a methoxyl group.

In another embodiment, formula VI compound is selected from:

Or its pharmacologically acceptable salts, solvate, ester or prodrug.

In another embodiment, formula I compound is expressed as with following formula VII:

Formula VII

Or its pharmacologically acceptable salts, wherein:

Z ¹⁰Be CH or N;

Z ¹¹Be CH ₂Or NH;

R ¹⁸And R ¹⁹With showing that the nitrogen-atoms that is connected with them is a heteroaryl, wherein when described heterocyclic radical had two substituting groups on adjacent carbons, the carbon atom that described substituting group connects with them formed 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ²⁰Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

S is 0,1 or 2.

In another embodiment, in formula VII, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹⁷R ¹⁸Heteroaryl is optional to be selected from following substituting group and to replace by one or more: heteroaryl and aryl.

In another embodiment, in formula VII, Z ¹⁰Be N.

In another embodiment, in formula VII, Z ¹¹Be CH.

In another embodiment, in formula VII, Z ¹¹Be CH ₂

In another embodiment, in formula VII, Z ¹¹Be NH.

In another embodiment, in formula VII, Z ¹⁰Be N, and Z ¹¹Be NH.

In another embodiment, in formula VII, Z ¹⁰Be N and Z ¹¹Be CH ₂

In another embodiment, in formula VII, Z ¹⁰Be CH and Z ¹¹Be CH ₂

In another embodiment, in formula VII, Z ¹⁰Be N, Z ¹¹Be NH, and s is 0.

In another embodiment, in formula VII, Z ¹⁰Be N, Z ¹¹Be CH ₂, and s is 1.

In another embodiment, in formula VII, Z ¹⁰Be CH, Z ¹¹Be CH ₂, and s is 1.

In another embodiment, in formula VII, in another embodiment, and in formula VII, Z ¹⁰Be N, Z ¹¹Be CH ₂, s is 1, and R ¹⁹Be-NH ₂

In another embodiment, in formula VII, Z ¹⁰Be CH, Z ¹¹Be CH ₂, s is 1, and R ¹⁹Be-NH ₂

In another embodiment, in formula VII ,-NR ¹⁸R ¹⁹Be pyrazolyl, it is optional substituted.

In another embodiment, in formula VII, optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹³R ¹⁴Heteroaryl is optional to be selected from following substituting group and to replace by one or more: optional thienyl that replaces and the optional aryl that replaces.

In another embodiment, formula VII compound is selected from:

Or its pharmacologically acceptable salts.

In another embodiment, formula I compound is expressed as with following formula VIII:

Formula VIII

Or its pharmacologically acceptable salts, wherein:

Z ¹¹Be CH or N;

Z ¹²Be CH ₂Or NH;

Each R ²¹Be H or alkyl independently;

R ²²Be aryl, wherein when described aryl had two substituting groups on adjacent carbons, the carbon atom that described substituting group connects with them formed 5-to 6-unit heterocyclic radical, aryl or heteroaryl;

R ²³Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

T is 0,1 or 2.

In another embodiment, in formula VIII, optional described R with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ²²Aryl is optional to be replaced by halogen.

In another embodiment, in formula VIII, Z ¹¹Be N.

In another embodiment, in formula VIII, Z ¹²Be CH.

In another embodiment, in formula VIII, Z ¹²Be CH ₂

In another embodiment, in formula VIII, Z ¹²Be NH.

In another embodiment, in formula VIII, Z ¹¹Be N, and Z ¹²Be NH.

In another embodiment, in formula VIII, Z ¹¹Be N and Z ¹²Be CH ₂

In another embodiment, in formula VIII, Z ¹¹Be CH and Z ¹²Be CH ₂

In another embodiment, in formula VIII, Z ¹¹Be N, Z ¹²Be NH, and t is 0.

In another embodiment, in formula VIII, Z ¹¹Be N, Z ¹²Be CH ₂, and t is 1.

In another embodiment, in formula VIII, R ²²Be phenyl, it is optional substituted.

In another embodiment, formula VIII compound is:

Or its pharmacologically acceptable salts.

The method for preparing The compounds of this invention

General method

Commercial solvent, reagent and the intermediate that obtains uses with the state of receiving.Not being commercial reagent that obtains and intermediate prepares in mode hereinafter described. ¹H NMR spectrum is to go up at VarianAS-400 (400MHz) to obtain, and with distance Me ₄The ppm of Si downfield gives a report, and wherein proton number, multiplicity and coupling constant (representing with Hz) are to indicate in the bracket mode.Proposing under the LC/MS data conditions, analyzing and use Applied Biosystems API-100 mass spectrograph and Shimadzu SCL-10A LC post to carry out: Altech platinum C18,3 microns, 33mmx7mm ID; Gradient flow quantity: 0min-10%CH ₃CN, 5min-95%CH ₃CN, 7min-95%CH ₃CN, 7.5min-10%CH ₃CN, 9min-stops.Use Agilent TechnologiesLC/MSD SL or 1100 serial LC/MSD mass spectrographs to obtain the MS data.By preparation type LC purifying final product, use the pillar of Varian Pursuit XRs C1810u 250x21.2mm, and the mixture of eluents of mobile phase A and B.Mobile phase A consists of the H of 0.1%TFA ₂O solution, Mobile phase B consists of CH ₃CN (95%)/H ₂O (5%)/TFA (0.1%).The mixture of mobile phase A and B at room temperature passes through the pillar wash-out with the flow velocity of 20mL/min.The purifying of all final isolated compound is to use the mixture of eluents of Higgins Haisil HLC185u150x4.6mm post and mobile phase A and B to detect by LCMS, and wherein mobile phase A consists of the H of 0.1%TFA ₂O solution, Mobile phase B consists of CH ₃CN (95%)/H ₂O (5%)/TFA (0.1%).Under 60 ℃ temperature with the flow velocity wash-out pillar of 3mL/min.It is by LCMS that midbody compound characterizes, and uses the mixture of eluents of Higgins Haisil HL C185u 50x4.6mm pillar and mobile phase A and B, and wherein mobile phase A consists of the H of 0.1%TFA ₂O solution, Mobile phase B consists of CH ₃CN (95%)/H ₂O (5%)/TFA (0.1%).Under 60 ℃ temperature with the flow velocity wash-out pillar of 3mL/min.

The method that is used for preparation formula I-VI compound is described as follows at different methods

Scheme 1 has illustrated the method for the intermediate amine compound of preparation formula 4.

Scheme 1

X wherein ^aBe F or Cl, and R ³And ring A is as mentioned at the definition of formula (I) compound.

In the presence of diisopropylethylamine (DIEA), heating or by using the microwave-assisted process, aryl that the nitro of formula 1 replaces or heteroaryl derivative can with the diethylenediamine compound coupling of formula 2, obtain the compound 3 of coupling.The nitro-compound of formula 3 can be used suitable method reduction then, obtain the intermediate amine compound of formula 4.

Embodiment-preparation intermediate 6:

Scheme 2

Intermediate 5:

Make 3-nitro-4-chloropyridine (10mmol) be dissolved in methylene dichloride (25mL), again diethyl isopropylamine (20mmol) is then added to Boc piperazine (10mmol) in the above-mentioned solution, simultaneously 0 ℃ of cooling down, and reaction mixture is at room temperature stirred spend the night.With the methylene dichloride vaporising under vacuum.Make the gained solid phase extraction in methylene dichloride, again with Citric Acid and salt brine solution washing.The evaporation methylene dichloride obtains yellow solid 4-(3-nitro-pyridin-4-yl)-piperazine-1-t-butyl formate, its not purified next step that promptly is used to.

Intermediate 6:

3-nitro-4-boc piperazinyl pyridine is dissolved in the ethyl acetate, adds several acetate again.Make gained solution stand Pd/C (10%, 10mol%), and remain under nitrogen atmosphere and the room temperature.Stirring is spent the night and the monitoring reaction process, finishes up to reaction.Make reaction soln pass through diatomite filtration, concentrate, obtain product 4-(3-amino-pyridine-4-yl)-piperazine-1-t-butyl formate, productive rate good (80%).

Intermediate 7:

Scheme 3

With 4-(3-amino-pyridine-4-yl)-piperazine-1-t-butyl formate (5.9g, 21.2mmol), 6-bromo-pyridine-2-formic acid (19.3g, 95.5mmol), O-(7-azepine benzo triazol-1-yl)-N, N, N ', and N '-tetramethyl-urea hexafluorophosphate (12.1g, 31.8mmol), (11.1ml, 63.6mmol) mixture in DMF (106ml) at room temperature stirs and spends the night diisopropylethylamine.Under vacuum, remove and desolvate, gained oil is placed ethyl acetate.Organic layer is then used the salt water washing with dilute hydrochloric acid, dilute sodium hydroxide, uses anhydrous sodium sulfate drying again.Remove and desolvate, obtain thickness oily matter, it by column chromatography purifying (SiO2,10% ethanol/methylene), is obtained compound 5 (the light brown solid of 8.3g, 85%).HPLC-MS t _R=3.25min (UV _254nm); Mass Calculation value at following formula: C ₂₀H ₂₄BrN ₅O ₃, 462.34, the LCMS m/z 462﹠amp of actual measurement; 464 (M+H).

The method for preparing the benzo lactam derivatives

Embodiment-preparation intermediate 10:

Scheme 4

Intermediate 8 (part A):

With 2-bromo-5-methoxyl group aryl carboxylic acid methyl esters (81.61mmol), trimethylammonium boroxine (13.36mL, 97.93mmol), Pd (dppf) Cl ₂(1.0g, 1.36mmol), diox (350mL), water (50mL) and Cs ₂CO ₃(22.5g 163mmol) stirred 16 hours under nitrogenize under 110 ℃ (oil baths).After the cooling, pass through solids removed by filtration.With this solution concentration, again by SGC purifying (10: the 1EtOAc/ hexane), obtain 8.

Intermediate 9:

Make compound 8 (4.4g 24.2mmol) is dissolved in tetracol phenixin (80mL), add N-bromosuccinimide (4.48g, 24.2mmol) and benzoyl peroxide (276mg, 1.13mmol).Reaction mixture was stirred 3 hours under refluxing, cross filter solid then, wash with ether again.The organic layer that merges is washed with water, use dried over sodium sulfate, concentrate, obtain the product 9 that needs).

Intermediate 10:

Compound 9 (124.0mmol) is dissolved among 7M ammonia/MeOH (150mL), in the sealing pressure bottle, under 60 ℃, stirs again and spend the night.Make the reaction mixture cooling, under reduced pressure remove again and desolvate.Resistates is suspended in ethyl acetate, restir 30 minutes.With solid filtering, be dissolved in methylene dichloride again.This methylene dichloride is washed with water, use dried over sodium sulfate, concentrate, obtain the product 10 that needs.

Embodiment-preparation intermediate 13:

Scheme 5

Intermediate 11:

With 2-bromo-5-methoxyl methyl benzoate (20.0g, 81.61mmol), the trimethylammonium boroxine (13.36mL, 97.93mmol), Pd (dppf) Cl ₂(1.0g, 1.36mmol), diox (350mL), water (50mL) and Cs ₂CO ₃(22.5g 163mmol) stirred 16 hours under nitrogen under 110 ℃ (oil baths).After the cooling, pass through solids removed by filtration.With this solution concentration, again by SGC purifying (10: the 1EtOAc/ hexane), obtain 11 (12.1g, 80%).Mass Calculation value at following formula: C ₁₀H12NO ₃, 180.20, LCMS m/z 181.20 (M+H) .NMR (H of actual measurement ¹); 2.35 (3H, CH3) 3.73 (3H ,-OCH3), 3.88 (3H, CO2-CH3), 6.86-7.5 (m, 3H, aromatic)

Intermediate 12:

Compound 11 (4.4g 24.2mmol) is dissolved in tetracol phenixin (80mL), add again N-bromosuccinimide (4.48g, 24.2mmol) and benzoyl peroxide (276mg, 1.13mmol).Reaction mixture was stirred 3 hours under refluxing, cross filter solid then, wash with ether again.The organic layer that merges is washed with water, use dried over sodium sulfate, concentrate, obtain the product 12 (6.1g, 98%) that needs.Mass Calculation value at following formula: C ₁₀H ₁₁BrO ₃259.10, the LCMS m/z 260 (M+H) of actual measurement, NMR (H ¹); 4.50 (2H, CH2-Br) 3.73 (3H ,-OCH3), 3.88 (3H, CO2-CH3), 6.86-7.5 (m, 3H, aromatic)

Intermediate 13:

(32.0g 124.0mmol) is dissolved in 7M ammonia/MeOH (150mL), stirs under 60 ℃ in the sealing pressure bottle and spends the night to make compound 12.Make the reaction mixture cooling, under reduced pressure remove and desolvate.Make resistates be suspended in ethyl acetate, restir 30 minutes.With solid filtering, be dissolved in methylene dichloride again.This methylene dichloride is washed with water, use dried over sodium sulfate, concentrate, obtain the product 13 (13.5g, 67%) that needs.Mass Calculation value at following formula: C ₉H ₉NO ₂, 163.17, the LCMS m/z 164.2 (M+H) of actual measurement, NMR (H ¹); 4.20 (2H, CH2) 3.73 (3H ,-OCH3), 3.88,6.86-7.5 (m, 3H, aromatic), 8.0 (NH)

Table in-1 compound 14-19 can the described similar test operation of embodiment synthesizes by following above basically.

Table 1

Intermediate 20:

Scheme 6

To 2-methyl-5-methyl sulfane base-phenylformic acid (250mg, 1.37mmol) TMSCHN2 of adding 2.74mmol in 1: 1 benzene/carbinol mixture of 10ml.Make reaction at room temperature stir 0.5hr.Remove and desolvate, the compound 20 that obtains 250mg is yellow oil (93%).This material is used without being further purified promptly.NMR (H ¹); 2.48 (s, 3H, CH3) 2.54 (s, 3H, SCH3), 3.88 (s, 3H, CO2-CH3), 7.10-7.8 (m, 3H, aromatic)

Intermediate 21:

Scheme 7

To 20 (1.034g, 5.27mmol) add in the solution in tetracol phenixin (15ml) N-bromosuccinic acid acid amides (0.935g, 5.27mmol) and benzoyl peroxide (47mg, 0.19mmol).With mixture heated overnight under refluxing.Solution leaches solid with ice-cooled.Remove and desolvate, obtain yellow oil, make it at excessive 7M NH ₃Under 70 ℃, stir in/methyl alcohol mesohigh the container and spend the night.Remove and desolvate, with the thick material of gained purifying (SiO2, ethane/ethyl acetate) on quick post, obtain compound 21 and be pale solid (158mg, 17%) .NMR (H again ¹); 2.51 (s, 3H, SCH3), 4.3 (s, 2H ,-CH2), 7.44-7.5 (m, 3H, aromatic).

Embodiment 22:

Scheme 8

To compound 20 (40mg, 0.223mmol) MCPBA of adding 0.223mg in the solution in the DCM of 5ml.Reaction mixture at room temperature stirred 3 hours.Crude product is washed with water, and organism concentrates under vacuum; Mass Calculation value at following formula: C9H9NO2S 195.04, and LCMS m/z 196.42 (M+H) product of actual measurement is used without being further purified promptly.

Intermediate 24:

Scheme 9

Intermediate 23:

(150mg 0.92mmol) is dissolved in DCM (20mL), is cooled to-78 ℃ again to make embodiment compound 13.In this mixture, drip BBr ₃(1M, 1.2mL).After 1 hour, make this mixture be warmed to room temperature, other 2 hours of restir.The BBr that adds another part then ₃(1M 1.2mL), extremely refluxes the gained mixture heating up again, and stirring is spent the night.After being cooled to room temperature, add EtOAc (100mL), Na is used in organism water, salt water washing ₂SO ₄Dry.After concentrating, this resistates promptly is used to next step without being further purified.HPLC-MS t _R=0.58min (UV _254nm); Mass Calculation value at following formula: C ₈H ₇NO ₂149.0, the LCMS m/z 150.1 (M+H) of actual measurement.

Intermediate 24:

(50mg 0.33mmol) adds to Cs with embodiment compound 23 ₂CO ₃(326mg, 1.0mmol), (HCl salt is 50mg) in the mixture in DMF (5mL) for 2-dimethyl aminoethyl muriate.With gained mixture heating up to 60 ℃, stirring is spent the night.After being cooled to room temperature,, desolvate with concentrating to remove again by removing by filter alkali.Resistates is crossed post, and (silica gel, DCM/MeOH=95: 5 to DCM/MeOH/Et3N=90: 5: 5), obtaining product 24 (53mg) is little yellow solid.HPLC-MS t _R=0.56min (UV _254nm); Mass Calculation value at following formula: C ₁₂H ₁₆N ₂O ₂220.1, the LCMS m/z 221.1 (M+H) of actual measurement.

Intermediate 25

Compound 25 in the table 2 is with above preparing at same operation described in the operation of intermediate 24.

Table 2

Intermediate 28

Scheme 10

Intermediate 26:

(2-fluoronitroarene, 6g 43mmol) have been dissolved in K with 2-fluorine nitroxide phenylarsine ₂CO ₃(12g, 86mmol) the exsiccant THF (80mL) in.This mixture is cooled to 0 ℃, add again amine (4.6g, 88mmol).The gained mixture is warmed to room temperature, restir 24 hours.Again this mixture is passed through diatomite filtration, concentrate.This resistates promptly is used to next step without being further purified.

Intermediate 27:

Make nitro-compound 26 (7.8g, thick material) be dissolved in THF (50mL), under argon gas, add again Pd/C (10%, 1g).With this mixture H ₂(40psi) handle restir 2 hours.Again this mixture is passed through diatomite filtration, concentrate under vacuum, obtain crude product 27, it promptly is used to next step without any being further purified.

Intermediate 28:

With compound 27 (7.0g, thick material) be dissolved in DMF (20mL) and CDI (6.5g, 40mmol).With this mixture heating up to 110 ℃, restir 2 hours.After being cooled to room temperature, under reduced pressure remove DMF by concentrating.(silica gel, DCM/MeOH=95: 5 to DCM/MeOH/Et with column purification for resistates ₃N=90: 5: 5), obtaining product 28 (5.2g) is little yellow solid

Preparation intermediate 31:

Scheme 11

Intermediate 29:

(6g 43mmol) is dissolved in and contains K with the 2-fluoronitrobenzene ₂CO ₃(12g is in dry THF 86mmol) (80mL).This mixture is cooled to 0 ℃, and adding amine (4.6g, 88mmol).The gained mixture is warmed to room temperature, restir 24 hours.Again this mixture is passed through diatomite filtration, concentrate.This resistates promptly is used to next step without being further purified.HPLC-MSt _R=0.77min (UV _254nm); Mass Calculation value at following formula: C ₁₀H ₁₅N ₃O ₂209.1, the LCMS m/z 210.1 (M+H) of actual measurement.

Intermediate 30:

Make nitro-compound 29 (7.8g, thick material) be dissolved in THF (50mL), under argon gas, add again Pd/C (10%, 1g).With this mixture H ₂(40psi) handle restir 2 hours.Again this mixture is passed through diatomite filtration, concentrate under vacuum, obtain crude product 30, it promptly is used to next step without any being further purified.HPLC-MS t _R=0.39min (UV ₂₅₄ _Nm); Mass Calculation value at following formula: C ₁₀H ₁₇N ₃179.1, the LCMS m/z 180.1 (M+H) of actual measurement.

Intermediate 31:

Make compound 30 (7.0g, thick material) be dissolved in DMF (20mL) and CDI (6.5g, 40mmol) in.With this mixture heating up to 110 ℃, restir 2 hours.After being cooled to room temperature, under reduced pressure remove DMF by concentrating.(silica gel, DCM/MeOH=95: 5 to DCM/MeOH/Et with column purification for resistates ₃N=90: 5: 5), obtaining product 31 (5.2g) is little yellow solid HPLC-MS t _R=0.57min (UV _254nm); Mass Calculation value at following formula: C ₁₁H ₁₅N ₃O205.1, the LCMS m/z 206.1 (M+H) of actual measurement.

Compound 32 usefulness in the table 3 are as same operation preparation as described in the intermediate 31.

Table 3

Intermediate 33:

Scheme 12

To 2-oxo-2,3-dihydro-1H-indoles-5-alkylsulfonyl muriate (800mg, 3.45mmol) add in the solution in 5mL DCM triethylamine (0.97mL, 6.90mmol), then add tetramethyleneimine (0.34mL, 4.14mmol).Reaction mixture at room temperature stirred 2 hours.Solid filtering with forming washs with DCM again.Under vacuum, collect and remove organic layer.Make gained oil be dissolved in ethyl acetate, anhydrous sodium sulfate drying is used in water and salt water washing then again.Remove and desolvate, obtain yellow solid, its purity is enough to reach former state and uses.HPLC-MS t _R=1.05min (UV _254nm); Mass Calculation value at following formula: C ₁₂H ₁₄N ₂O ₃S, 266.32, the LCMS m/z 267.30 (M+H) of actual measurement.

Intermediate 34:

Scheme 13

To 1-piperidin-4-yl-1, add tert-Butyl dicarbonate (1.26mL) and the solution of diisopropylethylamine (1.6mL) in 10ml DCM in the solution of 3-dihydro-benzimidazolyl-2 radicals-ketone (1.0g, 4.6mmol is in 10mL).This mixture was at room temperature stirred 1 hour.This mixture is washed with water, use anhydrous sodium sulfate drying again.Removing desolvates obtains white solid, purity good (95%).HPLC-MS t _R=1.61min (UV _254nm); Mass Calculation value at following formula: C ₁₇H ₂₃N ₃O ₃S, 317.38, the LCMS m/z 340.20 (M+Na) of actual measurement.

Intermediate 35:

Scheme 14

To 1, add tert-Butyl dicarbonate (1.26mL) and the solution of diisopropylethylamine (1.6mL) in 10ml DCM in the solution in 3-dihydro-1-(1,2,3,6-tetrahydrochysene-4-pyridyl)-2H-benzimidazolyl-2 radicals-ketone (4.6mmol is in 10mL).Mixture was at room temperature stirred 1 hour.This mixture is washed with water, use anhydrous sodium sulfate drying again.Removing desolvates obtains white solid, purity good (95%).HPLC-MS t _R=1.68min (UV _254nm); Mass Calculation value at following formula: C ₁₇H ₂₁N ₃O ₃S, 315.38, the LCMS m/z 316.20 (M+H) of actual measurement.

Intermediate 41:

Scheme-15

Part A:

Make 3, (1.77g 7.8mmol) is dissolved in DMF (10mL) to 4-dihydroxyl-diethyl phthalate, adds Cs again ₂CO ₃(2.55g, 7.8mmol).In this mixture, (1.2g 8.6mmol), at room temperature stirs the gained mixture and spends the night to add MeI.This mixture is diluted with EtOAc, and Na is used in water and salt water washing again ₂SO ₄Dry.After concentrating, with crude product column purification (silica gel, 15% to 30%EtOAc/ ethane), obtaining product 36 (698mg) is brown solid, reclaims initial substance (369mg).HPLC-MS tR=1.12min (UV254nm); Mass Calculation value at following formula: C ₁₁H ₁₂O ₆240.1, the LCMS m/z 241.1 (M+H) of actual measurement.

Part B:

(390mg 1.6mmol) is dissolved in THF (10mL) to make compound 36.With 2-methyl cellosolve (152mg, 2.0mmol) and PPh ₃(525mg 2.0mmol) adds in this mixture, again the gained mixture is cooled to 0 ℃.Dropping DIAD (404mg, 2.0mmol).Make this mixture be warmed to room temperature, stirring is spent the night.Add ether (50mL), leach solid.Under reduced pressure remove and desolvate, with resistates column purification (silica gel, 30%EtOAc/ ethane), obtaining product 37 (288mg) is brown solid again.HPLC-MS tR=1.60min (UV254nm); Mass Calculation value at following formula: C ₁₄H ₁₈O ₇298.1, the LCMS m/z 299.2 (M+H) of actual measurement.

Portion C:

(288mg 0.966mmol) is dissolved in THF (15mL), is cooled to 0 ℃ again to make compound 37.Add LiAlH ₄(1M in THF, 4.0mL).Make this mixture be warmed to room temperature, reflux then and spend the night.After being cooled to room temperature, carefully add H ₂O (152uL) adds 15%NaOH (152uL) and H again ₂O (456uL).This mixture is stirred other 30min, leach solid, wash with THF again.Under vacuum, this organism is concentrated, use column purification (silica gel, EtOAc～2%MeOH/EtOAc), obtain product 38 (155mg) again.HPLC-MS tR=1.00min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₈O ₅242.1, the LCMS m/z 225.1 (M-OH) of actual measurement.

Part D:

(155mg 0.64mmol) is dissolved in THF (15mL), adds PPh again to make compound 38 ₃(504mg, 1.92mmol).This mixture is cooled to 0 ℃, adds CBr again ₄(467mg, 1.4mmol).Make the gained mixture be warmed to room temperature, restir 2 hours.Leach solid, under vacuum, remove again and desolvate.Resistates obtains product 39 (192mg) with column purification (silica gel, 15%EtOAc/ ethane).

Part E:

(192mg 0.52mmol) is dissolved in DMF (5mL) to make dibromo compound 39.Add DIEA (260uL, 1.5mmol) and trityl group amine (148mg, 0.57mmol), again with this mixture heating up to 60 ℃, restir 2 hours.Under vacuum, remove DMF, again this resistates is placed EtOAc (60mL).Na is used in organism water and salt water washing ₂SO ₄Dry.After concentrating, resistates obtains product 40 (211mg) with column purification (silica gel, 30%EtOAc/ ethane).

Part F:

(211mg 0.45mmol) is dissolved in MeOH/CHCl to make compound 40 ₃In the mixture (5mL/5mL), be cooled to 0 ℃ again.The careful TFA (10mL) that adds.After 0 ℃ of following 5min, make this mixture be warmed to room temperature, the other 30min of restir.After concentrating, make resistates place ether and 1N HCl.Water extracts with ether, alkalizes to pH～10 with 4N NaOH then.This mixture is extracted with DCM (40mLx3).Make the organic phase drying of merging, concentrate.This crude product 41 (95mg) is directly used in next step and is not further purified.HPLC-MS tR=0.78min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₇NO ₃223.1, the LCMS m/z 224.2 (M-OH) of actual measurement.

Embodiment 46

Part A:

Compound 42 is to use the same terms preparation described among the embodiment 1 part B, part B of embodiment 1 part B, and this preparation starts from compound 3,4-dihydroxyl-Bisphthalate.HPLC-MS tR=1.45min (UV254nm); Mass Calculation value at following formula: C ₁₆H ₂₂O ₈342.1, the LCMS m/z 343.1 (M+H) of actual measurement.

Part B:

Compound 43 is to use the same terms preparation described in embodiment 41 portion C, and this preparation starts from compound 42.HPLC-MS tR=0.90min (UV254nm); Mass Calculation value at following formula: C ₁₄H ₂₂O ₆286.1, the LCMS m/z 269.2 (M-OH) of actual measurement.

Portion C:

Compound 44 is to use the same terms preparation described among the embodiment 41 part D, and this preparation starts from compound 43.

Part D:

Compound 45 is to use the same terms preparation described among the embodiment 41 part E, and this preparation starts from compound 44.

Part E:

Compound 46 is to use the same terms preparation described among the embodiment 41 part F, and this preparation starts from compound 45.HPLC-MS tR=0.80min (UV254nm); Mass Calculation value at following formula: C ₁₄H ₂₁NO ₄267.1, the LCMS m/z 268.1 (M+H) of actual measurement.

Embodiment 51:

Part A:

(240mg 1.0mmol) is dissolved in DMF (5mL) to make compound 36.Add Cs ₂CO ₃(325mg, 1.0mmol).This mixture is cooled to 0 ℃, is blown into BrCHF again ₂Reach 5min.Make the gained mixture be warmed to room temperature, stirring is spent the night.Add EtOAc (60mL), Na is used in water and salt water washing more then ₂SO ₄Dry.After concentrating, resistates obtains product 47 (271mg) with column purification (15～30%EtOAc/ ethane).HPLC-MS tR=1.69min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₂F ₂O ₆290.1, the LCMS m/z 291.1 (M+H) of actual measurement.

Part B:

Compound 48 is to use the same terms preparation described in embodiment 41 portion C, and this preparation starts from compound xxx.HPLC-MS tR=1.06min (UV254nm); Mass Calculation value at following formula: C ₁₀H ₁₂F ₂O ₄234.1, the LCMS m/z 257.0 (M+Na) of actual measurement.

Portion C:

Compound 49 is to use the same terms preparation described among the embodiment 41 part D, and this preparation starts from compound 48.

Part D:

Compound 50 is to use the same terms preparation described among the embodiment 41 part E, and this preparation starts from compound 49

Part E:

Compound 51 is to use the same terms preparation described among the embodiment 41 part F, and this preparation starts from compound 50.HPLC-MS tR=0.98min (UV254nm); Mass Calculation value at following formula: C ₁₀H ₁₁F ₂NO ₂215.1, the LCMS m/z 216.1 (M+H) of actual measurement.

Embodiment 52

The same operation method that provides among the embodiment 46 by preparation, the compound 52 that provides in can preparation table 4 hurdle 2, this preparation starts from 3,4-dihydroxyl-diethyl phthalate and BrCHF ₂

Table 4

Embodiment 55:

Part A

(2.66mL, 20mmol) (2.83g 94mmol) mixes in 33%HBr/HOAc (27mL) with Paraformaldehyde 96 to make the benzo dioxole under 0 ℃.Make this mixture be warmed to room temperature, restir spends the night.Remove under vacuum and desolvate, with resistates column purification (silica gel, 15%EtOAc/ ethane), obtaining product 53 (4.5g) is white solid.

Part B:

Compound 54 is to use the same terms preparation described among the embodiment 41 part E, and this preparation starts from compound 53.

Portion C:

Compound 55 is to use the same terms preparation described among the embodiment 41 part F, and this preparation starts from compound 54.HPLC-MS tR=0.54min (UV254nm); Mass Calculation value at following formula: C ₉H ₉NO ₂163.1, the LCMS m/z 164.1 (M+H) of actual measurement.

Embodiment 59

Part A:

To 3, (5.0g 23.29mmol) adds Et down at 0 ℃ in the solution in DCM (30mL) to 4-Dimethoxyphenyl Acetyl Chloride 98Min. ₃N (3.24mL, 23.29mmol), then add the aminoacetaldehyde dimethyl-acetal (2.51mL, 23.9mmol).Make this mixture be warmed to room temperature, restir 1 hour.Add EtOAc (300mL), with this organism water, salt water washing, use Na again ₂SO ₄Dry.After concentrating, this crude product 56 (6.5g) promptly is used to next step without being further purified.

Part B:

Make crude product 56 be dissolved in HOAc (30mL), add dense HCl (30mL) again from final step.This mixture at room temperature stirred spend the night.Under reduced pressure remove disacidify.Add entry (100mL), collect solid (compound 57) more after filtration, at air drying (4.4g).HPLC-MStR=1.05min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₃NO ₃219.1, the LCMS m/z 220.1 (M+H) of actual measurement.

Portion C:

Make compound 57 (4.4g) be dissolved in HOAc (100mL), under nitrogen, add 10%Pd/C (1g).At room temperature this mixture is stirred down at hydrogen (5bar) and spend the night.Leach Pd/C, concentrated filtrate.This resistates 58 (3.5g) is directly used in next step and is not further purified.HPLC-MS tR=0.91min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₅NO ₃221.1, the LCMS m/z 222.1 (M+H) of actual measurement.

Part D:

(3.5g 15.8mmol) is dissolved in THF (100mL), again this solution is heated to 45 ℃ to make lactan 58.The careful LiAlH that adds ₄(1N in THF, 32mL), refluxed the gained mixture 20 hours.After being cooled to room temperature, carefully add H ₂O (1.2mL) adds 15%NaOH (1.2mL) and H2O (3.6mL) again.This mixture of pin stirs other 30min, leaches solid, washs with THF again.This organism is concentrated under vacuum, and this crude product 59 (2.13g) promptly is used in the reaction without being further purified.HPLC-MS tR=0.62min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₇NO ₂207.1, the LCMS m/z 208.1 (M+H) of actual measurement.

Embodiment 62:

Part A:

Under argon gas, make compound 2, (216mg 2.0mmol) is dissolved in CCl to 3-diformazan pyrazine ₄(10mL), add 2,2 '-azo two (2-methyl propionitrile) (33mg, 0.2mmol) and NBS (356mg, 2.0mmol).This mixture was refluxed 16 hours.This mixture is filtered, use CCl again ₄Washing concentrates this filtrate, and (silica gel, EtOAc), obtaining product 60 (457mg) is yellow solid to use column purification again.HPLC-MS tR=1.34min (UV254nm); Mass Calculation value at following formula: C ₆H ₆Br ₂N ₂263.9, the LCMS m/z 264.9 (M+H) of actual measurement.

Part B:

Compound 61 is to use the same terms preparation described among the embodiment 41 part E, and this preparation starts from compound 69.

Portion C:

Compound 62 is to use the same terms of describing among the embodiment 41 part F from compound 61 preparations.HPLC-MS tR=0.22min (UV254nm); Mass Calculation value at following formula: C ₆H ₇N ₃121.1, the LCMS m/z 122.1 (M+H) of actual measurement.

Embodiment 65

Part A:

Under argon gas, will (370mg 2.0mmol) stirs 10 minutes down at 80 ℃ at the compound N among the DMF (20mL)-Boc-3-pyrrolidone.Add DMF-DMA (29.9ml) then.Above mixture was stirred 12 hours under uniform temp.Remove organic solvent, again this resistates is passed through the pillar purifying, obtain compound 63.

Part B:

Under argon gas, make Urethylane (514mg, 4.65mmol) and NaOEt (21%, in EtOH, 2.02mL) stir 15 minutes.Add then compound 63 (372mg, 1.55mmol).This mixture was stirred 3.5 hours down at 85 ℃.By 5% Citric Acid quencher, revaporization is to dry with reaction mixture.This resistates is dissolved in EtOAc, uses saturated NaHCO again ₃Solution, salt water washing, drying.After concentrating, this resistates by the pillar purifying, is obtained compound 64.HPLC-MS tR=1.48min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₇N ₃O ₃251.1, the LCMS m/z 252.1 (M+H) of actual measurement.

Portion C:

Compound 64 is dissolved in 1, among the 4N HCl in the 4-diox, at room temperature stirs 15 minutes again.After concentrating, this resistates 65 is directly used in next step and is not further purified.HPLC-MS tR=0.27min (UV254nm); Mass Calculation value at following formula: C ₁₂H ₁₇N ₃O ₃151.1, the LCMS m/z 152.1 (M+H) of actual measurement.

Intermediate 68:

Scheme 15

R wherein ¹As mentioned at the definition of formula (I) compound.(in above scheme 6, work as R ¹When being connected in nitrogen, in one embodiment, it has the R suc as formula II ⁶And R ⁷, the R of formula IV ¹¹And R ¹², the R of formula V ¹⁴And R ¹⁵And the R of formula VI ¹⁷And R ¹⁸Identical meanings)

2-bromine heteroaryl-6-carboxylic acid, ethyl ester (65) can with following reaction: (i) boronic acid compounds of formula 66, the (ii) boric acid 2 of formula 67,3-diformazan-2,3-butanediol ester compound or (iii) the zinc bromide compound or the (iv) amine (40) of formula 68, (the Buchwald/Hartwig reaction conditions is with the heteroaryl-6-ester intermediate of the 2-replacement of preparation formula 69 wherein to use suitable palladium coupling condition or Cu catalyzer and diamines.Can use LiOH to make formula 60 compound hydrolysis then, for example obtain the heteroaryl-6-carboxylic acid cpd of the 2-replacement of formula 71.

Embodiment 74

Following scheme 16 has illustrated the method for preparation formula (I) compound.

Scheme 16

R wherein ¹, R ², R ³With ring A as mentioned at the definition of formula (I) compound.

At N, under the existence of N-diisopropylethylamine, use 2-(1H-7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate (HATU), 2-bromo-heteroaryl-6-carboxylic acid can with the amine compound coupling of formula 65, obtain the amido intermediate of formula 72.Formula 72 compounds can use above described palladium catalytic process of scheme and R then ¹The group coupling obtains formula 73 compounds.Use acid for example TFA or formic acid from formula 73 compounds, remove the Boc blocking group, obtain the anilino bridged piperazine derivatives of formula (I).

Embodiment-preparation intermediate 74:

Scheme 17

The couling process of the HATU-that describes in operational version mediation, can make that the 2-of formula 71 replaces-heteroaryl-6-carboxylic acid and amine coupling, obtain the compound of structure 74.

Scheme 18

With 4-{3-[(6-bromo-pyridine-2-carbonyl)-amino]-pyridin-4-yl }-piperazine-1-t-butyl formate (xxx, 100mg, 0.22mmol), 6-methoxyl group-2,3-dihydro-isoindole-1-ketone, 1.2 equivalent, three (diphenylmethylene acetone) two palladiums (0) (20mg, 0.02mmol), Xantphos (26mg, 0.04mmol), (139mg, 0.66mmol) mixture heating up to 85 in 5ml De diox ℃ reaches 16 hours to potassiumphosphate.Make the gained suspension by filter to remove undissolved solid.Concentrate organic layer in a vacuum.This crude compound by preparation type LC purifying, is obtained compound 76.HPLC-MS tR=3.84min (UV254nm); Mass Calculation value at following formula: C ₂₉H ₃₂N ₆O ₅, 544.17, the LCMS m/z 545.20 of actual measurement.

Basically according to above preparation intermediate 76 described methodologys, can prepare the compound 77-124 that following table 5 is given.

Table 5

Compound 125:

Scheme 19

Make 0 ℃ of compound 76 (0.1mmol) cooling, be added in the 4N HCl in the diox, at room temperature stir 30min again.Under vacuum, remove diox, be dissolved in again in water-acetonitrile, freezing and low pressure is dry, obtain compound 125 and be powder.HPLC-MS tR=0.75min (UV254nm); Mass Calculation value at following formula: C ₂₄H ₂₄N ₆O ₃, 444.20.17, the LCMS m/z 445.20 of actual measurement

Compound 126-186

Basically according to intermediate 91 described methodologys, can synthesize the compound in the table 6.

Table 6

Compound 187-199 shown in the table 7 uses the similar operations preparation of describing in the operational version-16 basically.

Table-7

Intermediate 200:

Scheme 20

Make 4-{3-[(6-bromo-pyrrole shallow lake-2-carbonyl)-amino]-pyridin-4-yl }-piperazine-1-t-butyl formate (0.15mmol), 5-(4,4,5,5-tetramethyl--[1,3,2] two oxa-boron heterocycle pentane-2-yls)-cumarone (0.3mmol), 1,1 '-two (diphenylphosphine) ferrocene palladium (II) muriate (0.075mmol), the mixture of potassiumphosphate (0.45mmol) in the diox of 5mL in encloses container 90 ℃ of following heated overnight.Make this crude mixture pass through filter.Collected organic layer concentrates under vacuum.Thick material obtains compound 200 by preparation type LC purifying, and its MH+m/z is 500.22, and retention time is 3.88min.HPLC-MS tR=3.84min (UV254nm); Mass Calculation value at following formula: C ₂₈H ₂₉N ₅O ₄, 499.22, the LCMS m/z 500.22 of actual measurement

Intermediate 201-248

The embodiment 201-222 that table 8 is given can be basic synthesize according to the operation of describing among the embodiment 95.

Table 8

Compound 223:

Scheme 21

Make 0 ℃ of intermediate 200 (0.1mmol) cooling, be added in the 4N HCl in the diox again, at room temperature stir 30min again.Under vacuum, remove diox, be dissolved in again in water-acetonitrile, lyophilize, lyophilized obtains compound 223 and is powder.HPLC-MS tR=2.62min (UV254nm); Mass Calculation value at following formula: C ₂₃H ₂₁N ₅O ₂, 399.17, the LCMS m/z 400.20 of actual measurement

The compound 224-248 that table 9 is listed can be synthetic according to the described methodology of preparation (scheme-21) of compound 223 basically.

Table 9

Compound 251:

Scheme 22

Compound 249:

(317mg 2.0mmol) is dissolved in DMF (5mL), at room temperature adds DIEA (350uL to make compound 2-chloropyrimide-4-formic acid, 2.0mmol) and HATU (760mg, 2.0mmol), then add 4-(3-amino-pyridine-4-yl)-piperazine-1-t-butyl formate (556mg, 2.0mmol).This mixture at room temperature stirred spend the night.This mixture is diluted with EtOAc, and Na is used in water, salt water washing again ₂SO ₄Dry.After concentrating, (silica gel, EtOAc), obtaining product 249 (620mg) is brown solid with column purification with crude product.HPLC-MS t _R=1.18min (UV _254nm); Mass Calculation value at following formula: C ₁₉H ₂₃ClN ₆O ₃418.2, the LCMSm/z 419.2 (M+H) of actual measurement.

Compound 250:

2-chloropyrimide derivative 249 (50mg) and isoindoline (50mg) are dissolved in the acetonitrile (5mL), again with this mixture heating up to 80 ℃, restir 1 hour.Desolvate by concentrate removing, again with resistates by preparation type LC purifying, obtain compound 250.HPLC-MS t _R=1.63min (UV _254nm); Mass Calculation value at following formula: C ₂₉H ₃₅N ₇O ₅561.3, the LCMS m/z 562.3 (M+H) of actual measurement.

Compound 251:

Make compound 250 be dissolved in 10%TFA/DCM, at room temperature stir again and spend the night.After concentrating, resistates by preparation type LC purifying, is obtained compound 251.HPLC-MS t _R=0.89min (UV _254nm); Mass Calculation value at following formula: C ₂₄H ₂₇N ₇O ₃461.2, the LCMS m/z 462.2 (M+H) of actual measurement.

Compound 252-288:

Basically at the given same operation of the preparation of compound 252-288, can prepare compound 252-288 (being described in following table 10) from compound 2-chloro-pyrimidine-4-carboxylic acid.

Table 10

Preparation compound 290:

Scheme 23

Compound 289:

In the 25ml round-bottomed flask, pack into compound 249 (84mg, 0.2mmol), lactan (49mg, 0.3mmol), Pd ₂(dba) ₃(18mg, 0.02mmol), Xant-phos (23mg, 0.04mmol) and K ₃PO ₄(106mg 0.5mmol), adds diox (5mL).By making flask alternately be connected to vacuum and argon gas fully outgases this mixture.Then with this gained mixture 80 ℃ of following heated overnight, by EtOAc (40ml) dilution, use the salt water washing again.After concentrating, this resistates with preparation type LC purifying, is obtained product 289.HPLC-MS t _R=1.45min (UV _254nm); Mass Calculation value at following formula: C ₂₈H ₃₁N ₇O ₅545.2, the LCMSm/z 546.3 (M+H) of actual measurement.

Compound 290:

(4N in the Zai diox, 4mL) handles, and at room temperature stirs 10min with HCl with compound 289 (10mg).After concentrating,, obtain compound 290 with this resistates lyophilized drying.HPLC-MS t _R=0.85min (UV _254nm); Mass Calculation value at following formula: C ₂₃H ₂₃N ₇O ₃445.2, the LCMS m/z 446.1 (M+H) of actual measurement.

Embodiment 291-295:

Basically according at compound 290 described same operation, can prepare compound 291-295 (being described in following table 11) from compound 249.

Table 11

Preparation compound 297:

Scheme 24

Compound 296:

Make benzoglyoxaline (24mg, 0.2mmol) and NaH (9.6mg, 2.4mmol, 60%) be dissolved among the DMF (5mL), again this mixture was stirred 10 minutes.(84mg 0.2mmol) adds in the above solution with compound 249 then.Down stir 10 minute or more at 50 ℃ this mixture.Desolvate by concentrate removing, again with resistates by preparation type LC purifying, obtain compound 296.HPLC-MS t _R=1.58min (UV _254nm); Mass Calculation value at following formula: C ₂₉H ₃₅N ₇O ₅500.2, the LCMS m/z 501.2 (M+H) of actual measurement.

Compound 297:

Use above preparation compound 290 described the same terms to prepare compound 297.The HPLC-MS:t of compound 297 _R=0.85min (UV _254m); Mass Calculation value at following formula: C ₂₃H ₂₃N ₇O ₃400.2, the LCMS m/z 401.2 (M+H) of actual measurement.

Compound 298-309:

Basically according at preparation compound 297 described same operation, can prepare compound 298-309 (being described in following table 12) from compound 249.

Table 12

Compound 310:

Compound in the table-13 can be basically from intermediate 249 and corresponding urea preparation.

Table-13

Compound 312:

Scheme-25

Compound 311:

In 10mL microwave bottle, pack into compound 249 (100mg, 0.24mmol), cumarone-2-dihydroxyl borane (58mg, 0.36mmol), Pd (dppf) Cl ₂(19mg, 0.024mmol), triethylamine (73mg, 0.72mmol) and methyl alcohol (1mL).This mixture 120 ℃ of following radiation 30 minutes, is concentrated then, use eluent ethyl acetate with short silicagel column again, obtain crude compound 311.HPLC-MS t _R=0.93min (UV _254nm); Mass Calculation value at following formula: C ₂₂H ₂₀N ₆O ₂: 500.2; The m/z:501.2 (M+H) of actual measurement.

Compound 312:

This rough intermediate 311 is dissolved among the 10%TFA/DCM, at room temperature stirred 2 hours again, concentrate it this moment, by preparation type LC purifying, obtains compound 312 again.HPLC-MS t _R=1.61min (UV _254nm); Mass Calculation value at following formula: C ₂₂H ₂₀N ₆O ₂: 400.2; The m/z:401.2 (M+H) of actual measurement.

Compound 313-350:

By the same operation method that provides among the preparation embodiment 311, the compound 313-353 that can from compound 249 preparation table 14 hurdles 2, provide.

Table 14

Compound 354-397:

Basically by preparing the same operation method that provides among the embodiment 312 (part B), the compound 354-397 that can from compound 249 preparation table 15 hurdles 2, provide.

Table 15

Scheme-26

Compound 405:

Compound 403:

In 10mL microwave bottle, pack into compound 249 (100mg, 0.17mmol), 4-iodine pyrazoles (66mg, 0.34mmol), triethylamine (52mg, 0.51mmol) and acetonitrile (1mL).Make this mixture 120 ℃ of following radiation 30 minutes, concentrate then,, obtain intermediate 403 and be colorless solid again by silica gel chromatography purifying (100% ethyl acetate).HPLC-MS t _R=1.63min (UV ₂₅₄ _Nm); Mass Calculation value at following formula: C ₂₂H ₂₅IN ₈O ₃: 576.2; The m/z:577.2 (M+H) of actual measurement.

Compound 404:

In 10mL microwave bottle, pack into compound 403 (98mg, 0.17mmol), 4-p-methoxy-phenyl dihydroxyl borane (51mg, 0.34mmol), Pd (dppf) Cl ₂(14mg, 0.017mmol), triethylamine (52mg, 0.51mmol) and methyl alcohol (1mL).Make this mixture 120 ℃ of following radiation 30 minutes, concentrate then, use eluent ethyl acetate with short silicagel column again, obtain midbody compound 404.HPLC-MS t _R=1.58min (UV _254nm); Mass Calculation value at following formula: C ₂₉H ₃₂N ₈O ₄: 556.2; The m/z:557.2 (M+H) of actual measurement.

Compound 405:

Make midbody compound 404 be dissolved in 10%TFA/DCM, at room temperature stirred 2 hours again, concentrate it this moment, by preparation type LC purifying, obtains compound 405 again.HPLC-MSt _R=2.66min (UV _254nm); Mass Calculation value at following formula: C ₂₄H ₂₄N ₈O ₂: 456.2; The m/z:457.2 (M+H) of actual measurement.

Compound 406-408:

Basically by preparing the same operation method that provides among the embodiment 405 (part B), the compound 406-408 that can from compound 100 preparation table 16 hurdles 2, provide.

Table 16

Compound 409-412:

Basically by preparing the same operation method that provides among the embodiment 405 (part B), the compound 409-412 that can from compound 249 preparation table 17 hurdles 2, provide.

Table 17

Scheme-27:

Compound 417:

Compound 417

Compound 412:

To contain compound 1H-pyrazoles-4-methylamine (1g, 10.3mmol) and add in the flask of methylene dichloride (50mL) tert-Butyl dicarbonate (2.25g, 10.3mmol).Solution stirring is spent the night, slough solvent, finally by silica gel chromatography purifying (50: 50EtOAc/ ethane), obtain compound 412 and be colorless solid.HPLC-MS t _R=1.16min (ELSD); Mass Calculation value at following formula: C ₉H ₁₅N ₃O ₂: 197.1; The m/z:198.1 (M+H) of actual measurement.

Compound 413:

To contain 4-chloro-3-nitropyridine in DMF (30mL) (1g, 6.3mmol) and compound 412 (1.24g, add in flask 6.3mmol) sodium hydride (60%, be suspended in the mineral oil, 277mg, 6.9mmol).Reaction is stirred spend the night, use saturated NaHCO then ₃The solution quencher extracts with EtOAc again.This organic extract is concentrated, again by silica gel chromatography purifying (50: 50EtOAc/ ethane), obtain compound 413 and be colorless solid.HPLC-MS t _R=1.55min (UV _254nm); Mass Calculation value at following formula: C ₁₄H ₁₇N ₅O ₄: 319.1; The m/z:320.2 (M+H) of actual measurement.

Compound 414:

Make compound 413 (2g, 6.3mmol) solution in ethanol (100mL) is to advertise the Ar degassing, the 10%Pd/C (200mg) that packs into then is again at H ₂(1atm) stirred 8 hours down.Make reaction N ₂Bubbling cleans, and recycle silicon algae soil filters.Concentration response obtains compound 414 and is waxy solid.HPLC-MS t _R=0.91min (UV _254nm); Mass Calculation value at following formula: C ₁₄H ₁₉N ₅O ₂: 289.2; The m/z:290.2 (M+H) of actual measurement.

Compound 415:

Make compound 2-chloropyrimide-4-formic acid (317mg, 2.0mmol) with compound 414 (578mg, 2.0mmol) and HATU (760mg, 2.0mmol) mixing, be dissolved in then DMF (5mL) and DIEA (350uL, 2.0mmol) in.This mixture is at room temperature stirred a night, and dilute with water extracts with EtOAc more then.This organic extract is concentrated, again by silica gel chromatography purifying (50: 50EtOAc/ ethane), obtain compound 415 and be yellow solid.HPLC-MS t _R=0.234min (ELSD); Mass Calculation value at following formula: C ₁₉H ₂₀ClN ₇O ₃: 429.9; The m/z:430.9 (M+H) of actual measurement.

Compound 416:

In the 10mL microwave tube, make compound 415 (100mg, 0.23mmol) with 5,6-dimethoxy isoindoline (42mg, 0.23mmol), triethylamine (69mg, 0.69mmol) and acetonitrile (2mL) mixing.Under 100 ℃, make this solution radiation 30 minutes, with the EtOAc dilution, filter with short silicagel column more then, clean, obtain midbody compound 416 with EtOAc.HPLC-MS t _R=1.71min (UV _254nm); Mass Calculation value at following formula: C ₂₄H ₂₄N ₈O ₃: 572.3; The m/z:573.3 (M+H) of actual measurement.

Compound 417:

Make compound 416 be dissolved in 10%TFA/DCM.Stir after 2 hours, reaction is concentrated, by preparation type LC purifying, obtain compound 417 then.HPLC-MS t _R=3.00min (UV _254nm); Mass Calculation value at following formula: C ₂₄H ₂₄N ₈O ₃: 472.3; The m/z:473.3 (M+H) of actual measurement.

Compound 418:

Scheme-28:

Compound 418:

In 10mL microwave bottle, pack into the 5-bromo benzothiazole (214mg, 1mmol), two (pinacol) two boron (bis (pinacolato) diboron, 381mg, 1.5mmol), Pd (ddpf) Cl ₂(40mg, 0.05mmol), potassium acetate (490mg, 5mmol) and DMSO (5mL).Under 100 ℃, make this reaction radiation and stirred 30 minutes.Make to be reflected between water and the EtOAc and distribute.Organic phase is separated, concentrate, then by silica gel chromatography purifying (1: 9EtOAc/ ethane), obtain compound 418 and be waxy solid.HPLC-MS t _R=2.01min (ELSD); Mass Calculation value at following formula: C ₁₃H ₁₆BNO ₂S:261.1; The m/z:262.1 (M+H) of actual measurement.

Compound 419-421:

Basically the same operation method that provides among the embodiment 418 by preparation, the compound 419-421 that provides in can preparation table 18 hurdle 2.

Table 18

Preparation compound 426:

Scheme 29

Compound 423:

With embodiment 250 used identical amination condition synthetic compounds 423, this preparation starts from 2-chloro-4-methoxy pyrimidine-6-methyl-formiate.HPLC-MS t _R=1.87min (UV _254nm); Mass Calculation value at following formula: C ₁₇H ₁₉N ₃O ₅345.1, the LCMS m/z 346.1 (M+H) of actual measurement.

Compound 424:

Compound 423 (20mg) is mixed with dense HCl (1.5mL), this mixture was refluxed 1 hour.Concentrate to remove under vacuum and desolvate, this crude product 424 promptly is used to next step without any being further purified.HPLC-MS t _R=0.87min (UV _254nm); Mass Calculation value at following formula: C ₁₅H ₁₅N ₃O ₅317.1, the LCMS m/z 318.1 (M+H) of actual measurement.

Compound 425:

Compound 424 is to use the preparation of condition described in the embodiment 251, and this preparation starts from compound 424.HPLC-MS t _R=1.27min (UV _254nm); Mass Calculation value at following formula: C ₂₉H ₃₅N ₇O ₆577.3, the LCMS m/z 578.2 (M+H) of actual measurement.

Compound 426:

Compound 426 is to use the same terms preparation described among the scheme 22 part B, and this preparation starts from compound 425.HPLC-MS t _R=0.74min (UV _254nm); Mass Calculation value at following formula: C ₂₄H ₂₇N ₇O ₄477.2, the LCMS m/z 478.1 (M+H) of actual measurement.

Preparation compound 431:

Scheme 30

Compound 427:

(298mg 2.0mmol) is dissolved in exsiccant and contains Et to make dichloro pyrimidine ₃(280uL is among THF 2.0mmol) (10mL) for N.This mixture is cooled to 0 ℃, add again isoindoline (380mg, 2.1mmol).The gained mixture is warmed to room temperature, restir 3 hours.Add EtOAc to dilute this mixture, with this organism water, salt water washing, use Na again ₂SO ₄Dry.After concentrating, resistates column purification (silica gel, EtOAc/ ethane=30: 70), obtaining product 427 (311mg) is faint yellow solid.HPLC-MS t _R=1.49min (UV _254nm); Mass Calculation value at following formula: C ₁₄H ₁₄ClN ₃O ₂291.1, the LCMS m/z 292.1 (M+H) of actual measurement.

Compound 428:

(100mg 0.34mmol) is dissolved among the DMF (5mL), adds KCN (100mg) again to make compound 427.With this mixture heating up to 150 ℃, stirring is spent the night.After being cooled to room temperature, add EtOAc, with this organism water, salt water washing, use Na again to dilute this mixture ₂SO ₄Dry.After concentrating, resistates column purification (silica gel, EtOAc/ ethane=30: 70), obtaining product 428 (69mg) is faint yellow solid.HPLC-MS t _R=1.56min (UV _254nm); Mass Calculation value at following formula: C ₁₅H ₁₄N ₄O ₂282.1, the LCMS m/z 283.1 (M+H) of actual measurement.

Compound 429:

(28mg 0.1mmol) mixes with 15%NaOH (2mL), this mixture heating up is extremely refluxed restir 2 hours again to make compound 428.After being cooled to room temperature, add 6N HCl to regulate pH to 5～6.Filter to collect this solid (429), and use it in next step and be further purified without any.HPLC-MS t _R=0.76min (UV _254nm); Mass Calculation value at following formula: C ₁₅H ₁₅N ₃O ₄301.1, the LCMS m/z 282.2 (M+H) of actual measurement.

Compound 430:

Use described the same terms of embodiment to prepare compound 430 at preparation compound 250 (scheme-22).HPLC-MS t _R=1.22min (UV _254nm); Mass Calculation value at following formula: C ₂₉H ₃₅N ₇O ₅561.3, the LCMS m/z 562.2 (M+H) of actual measurement.

Compound 431:

Compound 431 is to use the same terms of description among the scheme 22 part B (preparation compound 251) to prepare, and this preparation starts from compound 430.HPLC-MS t _R=0.75min (UV ₂₅₄ _Nm); Mass Calculation value at following formula: C ₂₄H ₂₇N ₇O ₃461.2, the LCMS m/z 462.3 (M+H) of actual measurement.

Preparation compound 432:

Scheme 31

(184mg 1mmol) adds HATU (1.2 equivalent) in the solution in DMF (4ml) to compound 6-ethyl sulfenyl pyrazine-2 formic acid.Reaction mixture at room temperature stirred 10 minutes, added amine then, 4-(3-amino-pyridine-4-yl)-piperazine-1-t-butyl formate (333.6mg, 1.2 equivalents) and diisopropylethylamine (3 equivalent).Reaction mixture was at room temperature stirred 12 hours.Reaction mixture is concentrated under vacuum,, obtain compound 432 and be solid (310mg, 70% productive rate) again by column chromatography purifying (SiO2, ethane/ethyl acetate).HPLC-MS tR=1.25min (UV254nm); Mass Calculation value at following formula: C21H28N6O3S 444.19, the LCMS m/z 445.15 (M+H) of actual measurement.

Compound 433:

Scheme 32:

With compound 432 (93mg, 0.210mmol) and m-CPBA (51mg, 77%, 1.1mmol) mixture in DCM (3mL) at room temperature stirs 30min, uses EtOAc (100mL) dilution again.With this organism NaHCO ₃(saturated aqueous solution 20mlx2), the salt water washing, is used Na again ₂SO ₄Dry.After concentrating, this crude product 433 (90mg, 93%) is directly used in next step and is not further purified.HPLC-MS t _R=0.95min (UV _254nm); Mass Calculation value at following formula: C ₂₁H ₂₈N ₆O4S 460.19, the LCMS m/z 461.2 (M+H) of actual measurement.

Compound 434:

Scheme 33

At room temperature with compound 6-methoxyl group-2, the solution of 3-dihydro-isoindole-1-ketone (2 equivalent) in DMSO (1mL) was handled 15 minutes with NaH (60%, be suspended in the oil 2 equivalents).At room temperature compound 433 (1 equivalent) is added then so far in the solution, again this solution was at room temperature stirred 16 hours.The lcms analysis demonstration reacts completely.With reaction mixture saturated ammonium chloride (0.5mL) and acetonitrile (0.5mL) quencher.By preparation type LC purifying, obtain compound 434.HPLC-MS t _R=3.56min (UV _254nm); Mass Calculation value at following formula: C ₂₈H ₃₁N ₇O ₅545.24, the LCMS m/z 546.2 (M+H) of actual measurement.

Compound 435:

Scheme 34

To under vacuum, concentrate from the compound 434 of preparation type LC, again resistates is dissolved in diox (2mL).In this solution, add 4N HCl/ diox (2mL), restir 1 hour.After reacting completely (lcms analysis), concentrate, lyophilized obtains compound 435 and is solid.HPLC-MS t _R=0.9min (UV _254nm); Mass Calculation value at following formula: C ₂₃H23N ₇O ₃445.19, the LCMS m/z 446.2 (M+H) of actual measurement.

The compound 436 and 437 that following table 19 is listed is test details synthetic of describing at compound 432 to 435 by using basically.

Table 19

The compound 438 that table 20 is listed is the methodology synthetic according to compound 432 to 435 described information basically.

Table-20

Detect

CHK1SPA detects

The reorganization His-CHK1 that utilization is expressed in baculovirus expression system as the enzyme source and based on CDC25C biotinylation peptide as substrate (vitamin H-RSGLYRSP SMPENLNRPR) exploitation vitro detection method.

Material and reagent:

1) CDC25C Ser 216C-is called biotinylation peptide substrates (25mg), is stored in-20 ℃, and synthetic (Custom Synthesis by Research Genetics): vitamin H-RSGLYRSP is entrusted in research heredity SMPENLNRPR 2595.4MW

2) His-CHK1 In House lot P976,235 μ g/mL are stored in-80 ℃.

3) D-PBS (no CaCl and MgCl): GIBCO, Cat.#14190-144

4) SPA pearl: Amersham, the Cat.#SPQ0032:500mg/ bottle

The D-PBS of 10mL is added in the SPA pearl of 500mg working concentration with preparation 50mg/mL.Be stored in 4 ℃.Use in 2 weeks after the hydration.

5) white micro plate in 96-hole has bonded GF/B filter: Packard, Cat.#6005177

6) top sealing-96 hole adhesive films: Perkin Elmer, Cat.#6005185

7) the non-binding white polystyrene board in 96-hole: Corning, Cat.#6005177

8)MgCl2：Sigma，Cat.#M-8266

9)DTT：Promega，Cat.#V3155

10) ATP is stored in 4 ℃: Sigma, Cat.#A-5394

11)γ ³³P-ATP，1000-3000Ci/mMol：Amersham，Cat.#AH9968

12)NaCl：Fisher?Scientific，Cat.#BP358-212

13)H ₃PO ₄85％Fisher，Cat.#A242-500

14)Tris-HCL?pH?8.0：Bio-Whittaker，Cat.#16-015V

15) staurosporine (Staurosporine), 100 μ g:CALBIOCHEM, Cat.#569397

16) Hypure cell cultures level water, 500mL:HyClone, Cat.#SH30529.02

Reaction mixture:

1) kinase buffer liquid: 50mM Tris pH 8.0; 10mM MgCl ₂1mM DTT

2) His-CHK1, In House Lot P976, MW～30KDa is stored in-80 ℃.

Require 6nM with obtain～5, the positive control of 000CPM.For 1 plate (100rxn): 235 μ g/mL (the 7.83 μ M) stock solution of 8 μ L is diluted in the 2mL kinase buffer liquid.It is prepared into the 31nM mixture.Add 20 μ L/ holes.It is prepared into the end reaction concentration of 6nM.

3) CDC25C biotinylation peptide.

CDC25C is diluted to 1mg/mL (385 μ M) stock solution, is stored in-20 ℃.For 1 plate (100rxn): the 1mg/mL peptide stock solution of 10 μ L is diluted in the 2mL kinase buffer liquid.Obtain 1.925 μ M mixtures thus.Add 20 μ L/rxn.It is prepared into the end reaction concentration of 385nM.

4)ATP?Mix。

For 1 plate (100rxn): 1mM ATP (cold) stock solution and the fresh P33-ATP of 2 μ L (20 μ Ci) of 10 μ L are diluted in 5mL kinase buffer liquid.Obtain 2 μ M ATP (cold) solution thus; Add 50 μ L/ holes to start reaction.Final volume is 100 μ L/rxn, and end reaction concentration is 1 μ M ATP (cold) and 0.2 μ Ci/rxn thus.

5) stop bath:

Add for 1 plate: to 10mL cleaning buffer solution 2 (2M NaCl 1%H ₃PO ₄) in: 1mL SPA pearl slurries (50mg); Add 100 μ L/ holes

6) cleaning buffer solution 1:2M NaCl

7) cleaning buffer solution 2:2M NaCl, 1%H ₃PO ₄

Detecting operation:

^*The total reaction volume that detects. ^*The end reaction volume of reaction end (after adding stop bath).

1) compound is diluted in water/10%DMSO the concentration that needs-this can obtain 1% final DMSO concentration in rxn.10 μ L/rxn are assigned in the suitable hole.Add 10 μ L 10%DMSO to positive (CHK1+CDC25C+ATP) and negative (CHK1+ATP only) control wells.

2) melting enzyme-in kinase buffer liquid on ice is diluted to enzyme proper concn (referring to reaction mixture) and distributes 20 μ L to each hole.

3) melt the biotinylation substrate on ice, redilution is in kinase buffer liquid (referring to reaction mixture).Except negative control hole, add 20 μ L/ holes.In addition, add 20 μ L kinase buffer liquid in these holes.

4) in kinase buffer liquid, ATP (cold) and P33-ATP are diluted (referring to reaction mixture).Add 50 μ L/ holes to start reaction.

5) reaction was at room temperature carried out 2 hours.

6) by adding SPA pearl/stop bath (referring to reaction mixture) termination reaction of 100 μ L, hatched 15 minutes before collecting.

7) blank Packard GF/B filter plate is placed vacuum apparatus (Packard plate collector), suck 200mL water and pass through with wetting this system.

8) take out this blank plate and put into Packard GF/B filter plate.

9) the suction reaction is by this filter plate.

10) washing: 200mL washs each time; 1X 2M NaCl; 1X 2M NaCl/1%H ₃PO ₄

11) make the dry 15min of filter plate.

12) place closedtop-the stick to top of filter plate.

13) filter plate is counted in Top Count

Be provided with: data pattern: CPM

Active nucleus: manual SPA:P33

Scintillator: Liq/plast

Energy region: low

IC ₅₀ Measure: from the serial dilution of 8 points of inhibitor compound, draw dose response curve, a-type double according to the inhibition data that generate.Compound concentrations is drawn to the % kinase activity, and this % kinase activity is calculated divided by the CPM of untreated samples by the CPM that handles sample.In order to generate IC ₅₀Value fits to dose response curve the standard sigmoid curve then, derives IC by nonlinear regression analysis ₅₀Value.

CDK2 detects

Baculovirus makes up:By PCR cyclin E be cloned into pVL1393 (Pharmingen, La Jolla, California) in, add 5 histidine residues at N-terminal, with purifying on the nickel resin.Expressed proteins is approximately 45kDa.By PCR CDK2 is cloned among the pVL1393, adds hemaglutinin (haemaglutinin) epitope tag (YDVPDYAS) at C-terminal.The expressed proteins size is approximately 34kDa.

Enzyme produces:The recombinant baculovirus coinfection that makes express cell cyclin E and CDK2 with identical multiple infection reaches 48 hours to SF9 cell (MOI=5).By with centrifugal 10 minutes collecting cells of 1000RPM, molten born of the same parents' damping fluid with 5 times of throw out volumes makes throw out molten born of the same parents in ice reach 30 minutes then, this damping fluid contains 50mM Tris pH 8.0,150mM NaCl, 1%NP40,1mM DTT and proteinase inhibitor (Roche Diagnostics GmbH, Mannheim, Germany).Make lysate rotation 10 minutes with 15000RPM, keep supernatant liquor.With 5mL nickel bead (for 1 liter SF9 cell) in molten born of the same parents' damping fluid, wash 3 times (Qiagen GmbH, Germany).Imidazoles is added in the baculovirus supernatant liquor, and making ultimate density is 20mM, then 4 ℃ down and nickel bead hatched 45 minutes.With molten born of the same parents' buffer solution eluted protein matter, this molten born of the same parents' damping fluid contains the 250mM imidazoles.Make the elutriant dialysed overnight in 2 liters of kinase buffer liquid, this kinase buffer liquid contains 50mM Tris pH 8.0,1mM DTT, 10mM MgCl ₂, 100 μ M sodium orthovanadates and 20% glycerine.The enzyme portioning is preserved.

Cell in vitro cyclin E/CDK2 kinase assay

In low protein binding 96-orifice plate (Corning Inc, Corning, New York), carry out cyclin E/CDK2 kinase assay.Enzyme is diluted to the ultimate density of 50 μ g/mL in kinase buffer liquid, this kinase buffer liquid contains 50mM Tris pH 8.0,10mM MgCl ₂, 1mMDTT and 0.1mM sodium orthovanadate.The substrate that is used for these reactions for derive from histone h1 (from Amersham, biotinylation peptide UK).Make substrate melting on ice, in kinase buffer liquid, be diluted to 2 μ M again.Make the concentration that compound is diluted to be needed in 10%DMSO.For each kinase reaction, the 50 μ g/mL enzyme solution (enzyme of 1 μ g) of 20 μ L and the 2 μ M substrate solutions of 20 μ l are mixed, the compound with 10 μ L dilution merges in the hole that each is used for testing then.By adding 50 μ L of, 2 μ M ATP and 0.1 μ Ci of 33P-ATP (from Amersham, UK) starts this kinase reaction.Reaction was at room temperature carried out 1 hour.Come termination reaction by adding 200 μ L stop buffers, this damping fluid contains 0.1%Triton X-100, and 1mM ATP, 5mM EDTA and 5mg/mL streptavidine are coated with the SPA pearl of stain (from Amersham, UK) for is 15 minutes.Use Filtermate common collector (Packard/Perkin ElmerLife Sciences.) then, the SPA pearl is collected in the 96-well GF/B filter plate (Packard/PerkinElmer Life Sciences).By washing this pearl 2 times, wash this pearl 2 times with the 2M NaCl that contains 1% phosphoric acid then, to remove non-specific signal with 2M NaCl.Use TopCount 96 hole liquid scintillation counters (from Packard/Perkin Elmer LifeSciences) to measure emission signal then.

The MEK1 kinase assay

Baculovirus infection by the Hi-Five cell makes total length activation phosphorylation MEK1 be expressed as 6X histidine tagged protein (His ₆-MEK1), this Hi-Five cell and the baculovirus coinfection of expressing activatory Raf-1 on the unlabelled composition.Then with some milligrams activation His ₆-MEK1 is by Ni-NTA affinity chromatography purifying, then by the gel filtration chromatography purifying.Has the catalytic disactivation ERK2KR of the total length mouse that in the II of territory, subprovince, is mutated into arginic Methionin as substrate.IPTG-inductive BL21D3 intestinal bacteria, make ERK2KR be expressed as the fusion rotein of biotinylation 6X Histidine Trx mark from carrier pET32aRC,, then pass through Mono Q ion-exchange chromatogram purification again by Ni-NTA affinity chromatography purifying.Under 25 ℃, in 96 orifice plates, carry out kinase reaction and reach 15min with double, every hole 33 μ L, and this kinase reaction consist of 20nM His ₆-MEK1,2 μ M ERK2KR, 2 μ M ATP, 10 μ Ci/ μ L[γ- ³³P]-ATP, 10mM MgCl ₂, 0.01% β-octyl glucoside, 1mM DTT, 20mM HEPES pH 7.5,3%DMSO and scope be the test compounds that 20 μ M reduce to 0.08nM.Stop kinase reaction by the 1.5%o-phosphoric acid that adds 30 μ L, transfection is hatched and was made the ERK2KR combination in 5 minutes in Millipore Multiscreen-PH plate.React according to preincubate and to estimate non-specific activity, wherein the 1.5%o-phosphoric acid with 30 μ L adds in each hole, adds enzyme then.By with the vacuum filtration of 0.75%o-phosphoric acid with termination plate washing 3 times, then, air-dry again with 100% washing with alcohol 2 times.The scintillation mixed solution (cocktail) of 50 μ L is added in each hole, re-use the detection of Wallac Microbeta 1450JET scintillometer and be incorporated among the ERK2KR ³³P.Use ActivityBase computed in software percent inhibition, IC ₅₀With the Hill slope value.

General operation at the MEK1TdF detection

In the PCR plate of white 96-hole, make 1 μ M albumen and the compound that detects the micro-molar concentration (1-50 μ M usually) in the damping fluid (25mMHEPES, pH 7.4,300mM NaCl, 1mM DTT, 2%DMSO, Sypro Orange 5x) at 20 μ l.By the cleaning band plate is sealed, place again thermal cycler (Chromo4, BioRad) on.Monitoring fluorescence intensity with per 0.5 ℃ of increment from 25 ℃ to 95 ℃ between melting period.Data are outputed to the excel table, obtain TdF Kd value through the custom curve fitting algorithm again.The error that all TdF Kd values have is limited to～and 50%, reason is the uncertainty due to the bonded thermal content changes.

External aurora body TdF detects

Aurora body A detects

Aurora body A kinase assay is to carry out in lower protein bonded 384-orifice plate (Corning company).Whole reagent are being melted on ice.Test compounds is diluted to the concentration that needs in 100%DMSO.Each reactant comprises 8nM enzyme (aurora body A, Upstate catalogue #14-511), 100nM Tamra-PKAtide (molecular device, 5TAMRA-GRTGRRNSICOOH), 25 μ M ATP (Roche), 1mM DTT (Pierce) and kinase buffer agent (10mM Tris, 10mM MgCl2,0.01%Tween 20).For each reaction, will contain 14 μ L of TAMRA-PKAtide, ATP, DTT and kinase buffer agent, with the compound merging of 1 μ L dilution.By adding the enzyme of 5 μ L dilution, kinase reaction is begun.Reaction was at room temperature carried out 2 hours.By adding 60 μ L IMAP beads (bead was at incremental (94.7% buffer reagent A:5.3% buffer reagent B) 1X buffer reagent, among the 24mM NaCl in 1: 400) reaction is stopped.Behind other 2 hours, operational analysis device AD (molecular device company) measures the fluorescence polarization.

Aurora body B detects

Aurora body A kinase assay is to carry out in lower protein bonded 384-orifice plate (Corning company).Whole reagent are being melted on ice.Compound is diluted to the concentration that needs in 100%DMSO.Each reactant comprises 26nM enzyme (aurora body B, Invitrogen catalogue #pv3970), 100nM Tamra-PKAtide (molecular device, 5TAMRA-GRTGRRNSICOOH), 50 μ M ATP (Roche), 1mM DTT (Pierce) and kinase buffer agent (10mM Tris, 10mM MgCl ₂, 0.01%Tween 20).For each reaction, will contain 14 μ L of TAMRA-PKAtide, ATP, DTT and kinase buffer agent, with the compound merging of 1 μ L dilution.By adding the enzyme of 5 μ L dilution, kinase reaction is begun.Reaction was at room temperature carried out 2 hours.By adding 60 μ L IMAP beads (bead was at incremental (94.7% buffer reagent A:5.3% buffer reagent B) 1X buffer reagent, among the 24mM NaCl in 1: 400) reaction is stopped.Behind other 2 hours, operational analysis device AD (molecular device company) measures the fluorescence polarization.

IC ₅₀Measure

Dose-response curve is 8 serial dilutions from test compounds, from the inhibition data mapping that respectively repeats to produce.Compound concentrations is mapped to kinase activity, and this kinase activity is to calculate by fluorescence polarization degree to get.In order to produce IC ₅₀Value then makes dose-response curve fit to standard S shape curve, and derives IC by nonlinear regression analysis ₅₀Value.

The Chk1 IC that The compounds of this invention has ₅₀The scope of value is that about 1nM is to about 50 μ M or higher, Chk2IC ₅₀The scope of value is that about 0.8 μ M is to about 50 μ M or higher, CDK2IC ₅₀The scope of value is extremely about 50 μ M or higher of about 2.3 μ M, and Chk1EC ₅₀The scope of value is that about 0.15 μ M is to about 1.5 μ M or higher.

The compounds of this invention can be used for treatment or prevention proliferative disease, for example cancer; Autoimmune disease; Virus disease; Fungal disease; Neuroscience or neurodegenerative disorders (for example, Ah ear is grown extra large Mo's disease or Parkinson's disease); Sacroiliitis; Inflammation; The local asphyxia damage; Anti-hyperplasia illness (for example eye retinopathy); Sacred disease; Alopecia; Or cardiovascular disorder.Can include but not limited to U.S. Patent No. 6,413 by specified disease and the illness of using the treatment of at least a The compounds of this invention, those disclosed in 974, it incorporates this paper by reference into.

The compounds of this invention has pharmacological property.In one embodiment, The compounds of this invention (be formula I-VI those) can be inhibitors of protein kinases, conditioning agent or modulator.Therefore, The compounds of this invention can be used for treating or preventing disease and the illness relevant with the activity of one or more protein kinases.Can suppress by The compounds of this invention, the limiting examples of adjusting or synthetic protein kinase comprises cyclin-dependent kinase (CDK), for example CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8; Aurora body kinases is aurora body-A, aurora body-B and aurora body-C for example; Mitogen activation of protein kinases (MAPK/ERK); Glycogen synthase kinase 3 (GSK3 β); C-Met kinases, for example c-Met; The Pim-1 kinases; Check point kinases, for example Chk1 and Chk2; Tyrosylprotein kinase, for example the HER subtribe (for example comprises, EGFR (HER1), HER2, HER3 and HER4), Regular Insulin subtribe (comprising for example INS-R, IGF-IR, IR and IR-R), PDGF subtribe (comprising for example PDGF-α and beta receptor, CSFIR, c-kit and FLK-II), FLK family (comprising that for example kinases insertion functional part acceptor (KDR), fetus liver kinases-1 (FLK-1), fetus liver kinases-4 (FLK-4) reach like fms Tyrosylprotein kinase-1 (flt-1)); Non-receptor protein tyrosine kinases, for example LCK, Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK; And growth factor receptor tyrosine kinase, for example VEGF-R2, FGF-R, TEK, AKT kinases etc.

The compounds of this invention can be used for suppressing the kinase whose oncogene of coded protein.The limiting examples of this type of oncogene comprises C-Met.

The compounds of this invention can be used for treatment or prevention proliferative disease.Can include but not limited to cancer, atherosclerosis, sacroiliitis, psoriasis, idiopathic pulmonary fibrosis, scleroderma and liver cirrhosis according to the illustrative example of the inventive method treatment or the proliferative disease that prevents.

Because CDK generally keying action in regulating hyperplasia, inhibitor can be used as the reversible cytostatic agent, it can be used for treatment and is characterized as the outgrowth any lysis of abnormal cells, for example, restenosis, hypertrophic cicatrix formation, inflammatory bowel, transplant rejection, endotoxin shock and the fungi infestation behind benign prostatic hyperplasia, familial adenomatous polyposis disease, multiple neurofibromatosis, atherosclerosis, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, angioplasty or the vascular surgery.

The compounds of this invention also can be used for treating Ah ear and grows extra large Mo's disease, as participated in pointed (J.Biochem, (1995) of recent findings of tau protein matter phosphorylated effect by CDK5 117, 741-749).

The compounds of this invention can bring out or suppress apoptosis.Apoptosis is replied superstition in multiple human diseases.The compounds of this invention as apoptotic modulator will can be used for treating cancer (including but not limited to type referred to above), virus infection (includes but not limited to simplexvirus (herpevirus), poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), the AIDS development of the individual philtrum that prevention HIV infects, autoimmune disease (includes but not limited to systemic lupus erythematosus, systemic lupus erythematosus (erythematosus), the glomerulonephritis that autoimmunization mediated, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes), neurodegenerative disorders (includes but not limited to that Ah ear grows extra large Mo's disease, the dementia that AIDS is relevant, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellum degeneration), myelodysplastic syndrome, aplastic anemia, form relevant ischemia injury with myocardial infarction, apoplexy and reperfusion injury, irregularity of pulse, atherosclerosis, the hepatopathy that toxin brings out or alcohol is relevant, blood disease (including but not limited to chronic anaemia and aplastic anemia), the degenerative disease of musculoskeletal system (including but not limited to osteoporosis and sacroiliitis), the aspirin sensitive sinusitis paranasal sinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

Can modulate cell RNA and DNA synthetic level as the The compounds of this invention of CDK inhibitor.Therefore, this type of medicament can be used for treating virus infection (including but not limited to HIV, Human papilloma virus HPV, simplexvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus).

The compounds of this invention also can be used as other inhibitors of protein kinases, for example protein kinase C, her2, raf1, MEK1, map kinase, EGF acceptor, pdgf receptor, IGF acceptor, PI3 kinases, wee1 kinases, Src, Abl, and therefore effective treatment and other protein kinase diseases associated.

Therefore, one aspect of the present invention is the method for treatment patient disease or illness, wherein this disease or illness are relevant with one or more protein kinases, this method comprises at least a The compounds of this invention to described patient's administering therapeutic significant quantity, or its pharmacologically acceptable salts, solvate, ester or prodrug.

In special embodiment, The compounds of this invention can be used for treatment or prevents multiple cancer and metastasis thereof, and include, but is not limited to following: the cancer knurl comprises bladder cancer, breast cancer, colorectal carcinoma, kidney, liver cancer, lung cancer comprises small cell lung cancer, nonsmall-cell lung cancer, head and neck cancer, esophagus cancer, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma comprise squamous cell carcinoma; Lymphatic system hematopoiesis tumour comprises leukemia, acute lymphoblastic leukemia, lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphomas, non-Hodgkin lymphomas, galley proof cell lymphoma, adventitial cell lymphoma, bone marrow cell carcinoma and Burkett lymphomas; Myeloid lineage hematopoiesis tumour comprises acute and chronic lymphocytic leukemia, myelodysplastic syndrome and progranulocyte leukemia; Between the tumour of matter origin, comprise fibrosarcoma and rhabdosarcoma; Maincenter and peripheral nervous system tumour comprise brain tumor for example astrocytoma, neuroblastoma, neurospongioma (for example glioblastoma multiforme) or schwannoma; And other tumour, comprise melanoma, spermocytoma, teratocarcinoma, osteosarcoma, different skin painted (xenoderoma pigmentosum), molluscum pseudocarcinomatosum (keratoctanthoma), Tiroidina follicular carcinoma and Kaposi sarcoma.The compounds of this invention can be used for treating primary tumor and/or metastatic tumo(u)r.

The compounds of this invention also can be used for the chemoprophylaxis of cancer.It is by blocking initial mutagenesis incident that chemoprophylaxis is defined as, or the progress of the preceding malignant cell of having been invaded by blocking-up, and suppresses the development of invasive cancer, or suppresses tumor recurrence.

The compounds of this invention also can be used for suppressing tumor-blood-vessel growth and transfer.

The compounds of this invention also can and with (together or sequential application) one or more anticancer therapy methods, for example radiotherapy, and/or at least a carcinostatic agent that is different from The compounds of this invention.The compounds of this invention can be present in the same dose unit as carcinostatic agent, or in isolating dose unit as carcinostatic agent.

Another aspect of the invention is the method for one or more and cell cycle protein dependent kinase diseases associated of treatment, it comprises that the patient to the treatment of this kind of needs uses a certain amount of first compound, it is a formula I-VI compound, or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer; And a certain amount of at least a second compound, this second compound is the carcinostatic agent that is different from The compounds of this invention, wherein the amount of first compound and second compound can produce result of treatment.

Be applicable to that the limiting examples (also being called antineoplastic agent) with the other carcinostatic agent of The compounds of this invention and usefulness comprises cytostatic agent, cytotoxic agent (such as but not limited to DNA agent interfering (for example cis-platinum or Zorubicin)); Taxanes (for example taxotere (taxotere), taxol); Topoisomerase II inhibitor (for example Etoposide or teniposide); Topoisomerase I inhibitor (for example Rinotecan (or CPT-11), camptostar or Hycamtin); Tubulin agent interfering (for example taxol, docetaxel (docetaxel) or Ai Boxi ketone (epothilones)); Hormone preparation (for example tamoxifen); Thymidylic acid (thymidilate) synthetase inhibitors (for example 5 FU 5 fluorouracil); Antimetabolite (for example Rheumatrex (methoxtrexate)); Alkylating agent (Temozolomide (TEMODAR for example ^TM, derive from Schering-Plough Corporation, Kenilworth, New Jersey), endoxan); Farnesyl protein transferase inhibitors (for example, SARASAR ^TM(4-[2-[4-[(11R)-3,10-two bromo-8-chloro-6,11-dihydro-5H-benzo [5,6] encircle heptan [1,2-b] pyridine-11-yl]-piperidino]-the 2-oxoethyl]-the 1-piperidyl urea, perhaps SCH 66336, derive from Schering-Plough Corporation, Kenilworth, New Jersey), tipifarnib ( Or R115777, derive from Janssen Pharmaceuticals), L778,123 (farnesyl protein transferase inhibitors derives from Merck﹠amp; Company, Whitehouse Station, New Jersey), BMS 214662 (farnesyl protein transferase inhibitors derives from Bristol-Myers Squibb Pharmaceuticals, Princeton, NewJersey); (for example, Iressa (derives from Astra ZenecaPharmaceuticals, England), antibody (for example, C225), the GLEEVEC of Tarceva (EGFR kinase inhibitor), EGFR to signal transduction inhibitor ^TM(the C-abl kinase inhibitor derives from NovartisPharmaceuticals, East Hanover, New Jersey); Interferons for example, intron (deriving from Schering-Plough Corporation), Peg-Intron (deriving from Schering-PloughCorporation); The hormonotherapy combined method; The aromatase enzyme combined method; Ara-C, AC and gemcitabine.

Other useful other carcinostatic agent include but not limited to uracil mustard, mustargen, ifosfamide (ifosfamide), L-PAM, Chlorambucil, pipobroman (Pipobroman), Persistol, ara-C, AC, Rimonophenazine ( Derive from Genzyme Oncology, Cambridge, Massachusetts), CldAdo (

Derive from Janssen-Cilag Ltd.), aphidicolon, B cell monoclonal antibody (B cell monoclonal antibody) (deriving from Genentech/Biogen Idec), sunitinib (

Derive from Pfizer), dasatinib (or BMS-354825, derive from Bristol-Myers Squibb), tezacitabine (deriving from Aventis Pharma), Sml1, fludarabine (deriving from Trigan Oncology Associates), pentostatin (deriving from BC Cancer Agency), triapine (deriving from VionPharmaceuticals), didox (deriving from Bioseeker Group), trimidox (deriving from ALSTherapy Development Foundation), amidox, 3-AP (3-aminopyridine-2-formyl thiosemicarbazone), MDL-101,731 ((E)-2 '-deoxidation-2 '-(fluorine methylene radical) cytidine) and gemcitabines.

Other useful other carcinostatic agent includes but not limited to triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, oxaliplatin, formyl tetrahydrofolic acid, oxaliplatin (ELOXATIN ^TMDerive from Sanofi-SynthelaboPharmaceuticals, France), pentostatin, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Zorubicin, epirubicin, idarubicin (Idarubicin), mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide, 17 alpha-acetylenes estradiol, diethylstilbestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium, Emcyt, the Zytron acetic ester, Leuprolide, Drogenil, toremifene, goserelin, cis-platinum, carboplatin, oxaliplatin, Aroplatin, hydroxyurea, Amsiacrine, procarbazine, mitotane (Mitotane), mitoxantrone, L-tetramisole, nvelbine, Anastrozole (Anastrazole), letrozole (Letrazole), capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, white arsenic (Trisenox), xeloda (Xeloda), vinorelbine, porfimer (Profimer), Erbitux, liposome (Liposomal), thio-tepa, hexamethyl melamine, L-PAM, trastuzumab, Lerozole, fulvestrant, Exemestane, fulvestrant, Ifosfomide, Rituximab, C225 and Campath.

If be deployed into fixed dosage, then this kind combination product adopts the The compounds of this invention in dosage range described herein, and other pharmaceutical active or medicine in its dosage range.For example, found that CDC2 inhibitor Ou Luomuxin (olomucine) can bring out on the apoptosis, produced synergy (J.Cell Sci., (1995) with known cytotoxic agent 108, 2897).When combination formula is inappropriate, The compounds of this invention also can with known anticancer agents or cytotoxic agent sequential application.The present invention does not limit the order of using; The compounds of this invention can use preceding of known anticancer agents or cytotoxic agent or after use.For example, the cytotoxic activity of cyclin-dependent kinase inhibitor flavones pyridine alcohol (flavopiridol) is subjected to influencing with the order that carcinostatic agent is used.Cancer?Research，(1997) 57，3375。This kind technology is in those skilled in the art and working doctor's technical scope.

Therefore, in one aspect, the present invention includes and be used for the treatment of patient's method for cancer, this method comprises to described patient uses a certain amount of at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer, and one or more other anticancer therapy forms, wherein the amount of The compounds of this invention/other form of therapy can produce the result of treatment that needs.In one embodiment, this at least a The compounds of this invention and these one or more other form of therapy play synergy.In one embodiment, this at least a The compounds of this invention and these one or more other form of therapy play synergism.

In one embodiment, this other form of therapy is operation.

In another embodiment, this other form of therapy is a radiotherapy.

In another embodiment, this other form of therapy is a biotherapy, for example hormonotherapy or anti-cancer vaccine therapy.

In another embodiment, the invention provides and suppress the kinase whose method in one or more check points in the patient who needs is arranged, it comprises at least a The compounds of this invention of this patient's administering therapeutic significant quantity or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

Another aspect of the present invention is treatment and one or more check point kinases diseases associated or delay the method for this progression of disease in the patient who needs is arranged, and it comprises at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or the steric isomer of administering therapeutic significant quantity.

Of the present invention be on the other hand again treatment one or more with the method for check point kinases diseases associated, it comprises to there being this patient who treats needs to use at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer; And at least a other carcinostatic agent, wherein the volume production of this at least a The compounds of this invention and this at least a carcinostatic agent is given birth to result of treatment.

Another aspect of the present invention is treatment and one or more check point kinases diseases associated or delay the method for this progression of disease in the patient who needs is arranged, it comprises the medical composition of administering therapeutic significant quantity, and this medical composition comprises the combination of at least a pharmaceutically acceptable carrier and at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

In above method, the check point kinases that suppress can be Chk1 and/or Chk2.

Another aspect of the present invention is the method that suppresses one or more Tyrosylprotein kinases in the patient who needs is arranged, and it comprises at least a The compounds of this invention of this patient's administering therapeutic significant quantity or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

Of the present invention is treatment and one or more Tyrosylprotein kinase diseases associated or delay the method for this progression of disease in the patient who needs is arranged again on the other hand, and it comprises at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or the steric isomer of administering therapeutic significant quantity.

Another aspect of the present invention be treatment one or more with the method for Tyrosylprotein kinase diseases associated, it comprises to there being this patient who treats needs to use at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer; And at least a other carcinostatic agent, wherein the volume production of this at least a The compounds of this invention and this at least a carcinostatic agent is given birth to result of treatment.

Another aspect of the present invention is treatment and one or more Tyrosylprotein kinase diseases associated or delay the method for this progression of disease in the patient who needs is arranged, it comprises the medical composition of administering therapeutic significant quantity, and this medical composition comprises the combination of at least a pharmaceutically acceptable carrier and at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

In above method, this Tyrosylprotein kinase can be VEGFR (VEGF-R2), EGFR, HER2, SRC, JAK and/or TEK.

Another aspect of the present invention is to suppress the kinase whose method of one or more Pim-1 in the patient who needs is arranged, and it comprises at least a The compounds of this invention of this patient's administering therapeutic significant quantity or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

Of the present invention is treatment and one or more Pim-1 kinases diseases associated or delay the method for this progression of disease in the patient who needs is arranged again on the other hand, and it comprises at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or the steric isomer of administering therapeutic significant quantity.

Another aspect of the present invention be treatment one or more with the method for Pim-1 kinases diseases associated, it comprises to there being this patient who treats needs to use at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer; And at least a other carcinostatic agent, wherein the volume production of this at least a The compounds of this invention and this at least a carcinostatic agent is given birth to result of treatment.

Another aspect of the present invention is treatment and one or more Pim-1 kinases diseases associated or delay the method for this progression of disease in the patient who needs is arranged, it comprises the medical composition of administering therapeutic significant quantity, and this medical composition comprises the combination of at least a pharmaceutically acceptable carrier and at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

Another aspect of the present invention be treatment one or more with the method for aurora body kinases diseases associated, it comprises to there being this patient who treats needs to use at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer; And at least a other carcinostatic agent, wherein the volume production of this at least a The compounds of this invention and this at least a carcinostatic agent is given birth to result of treatment.

Another aspect of the present invention is treatment and one or more aurora body kinases diseases associated or delay the method for this progression of disease in the patient who needs is arranged, it comprises the medical composition of administering therapeutic significant quantity, and this medical composition comprises the combination of at least a pharmaceutically acceptable carrier and at least a The compounds of this invention or its pharmacologically acceptable salts, solvate, ester, prodrug or steric isomer.

The pharmacological property of The compounds of this invention can be confirmed by multiple pharmacology detection method.Hereinafter the pharmacology detection method of the illustrative of Miao Shuing has been used according to compound of the present invention and salt, solvate, ester or prodrug and has been carried out.

The invention still further relates to medical composition, it comprises at least a The compounds of this invention, or the pharmacologically acceptable salts of this compound, solvate, ester or prodrug, and at least a pharmaceutically acceptable carrier.

For for compound medical composition of the present invention, inert, pharmaceutically acceptable carrier can be solid or liquid.But the solid form preparation comprises powder agent, tablet dispersible granule, capsule, cachet and suppository.Powder agent and tablet can comprise about 5 active ingredients to about 95 per-cents.Suitably solid carrier is known in the art, for example magnesiumcarbonate, Magnesium Stearate, talcum, sugar or lactose.Tablet, powder agent, cachet and capsule can be used as and be suitable for Orally administered solid dosage use.The example of pharmaceutically acceptable carrier and the method for making of various compositions can be consulted A.Gennaro (ed.), Remington ' s PharmaceuticalSciences, 18 ^ThEdition, (1990), Mack Publishing Co., Easton, Pennsylvania.

Liquid form preparation comprises solution, suspension and emulsion.Below as an example, it is non-through enteral administration to point out that water or water-propylene glycol solution are used for, or adds sweetener and opalizer, to be used for oral liquid, suspension and emulsion.Liquid form preparation also can comprise the solution for intranasal administration.

The aerosol preparations that is applicable to suction can comprise solution and be the solid of powder type that it can and use pharmaceutically acceptable carrier, for example inertia pressurized gas, for example nitrogen.

Also comprise the solid form preparation, it is intended to be converted to liquid form preparation using not long ago, uses through intestines for oral or non-.This kind liquid form comprises solution, suspension and emulsion.

The compounds of this invention can also transmit through the skin mode.Transdermal composition can be taked the form of emulsifiable paste, lotion, aerosol and/or emulsion, and can be comprised in the transdermal patch of matrix or reservoir type, and it is this area usual manner for this purpose.

The compounds of this invention can also subcutaneous mode transmit.

Compound preferably with in per os mode or intravenously or the sheath or mode of their some suitable combination use.

This pharmaceutical preparation preferably is unit dosage.In this kind form, preparation is subdivided into the unitary dose of suitable size, and it contains the active ingredient of appropriate amount, for example reaches required purpose significant quantity.

The amount of active compound in unit dose formulations can change or be adjusted into about 0.001mg to about 500mg.In one embodiment, the amount of active compound in unit dose formulations is that about 0.01mg is to about 250mg.In another embodiment, the amount of active compound in unit dose formulations is that about 0.1mg is to about 100mg.In another embodiment, the amount of active compound in unit dose formulations is that about 1.0mg is to about 100mg.In another embodiment, the amount of active compound in unit dose formulations is that about 1.0mg is to about 50mg.In another embodiment again, the amount of active compound in unit dose formulations is about 1.0mg about 25mg extremely.

The actual dose that is adopted can change according to patient's requirement and by the seriousness of treatment symptom.Determine that the suitable dosage instructions about how to take medicine for particular condition are in the skill of this area.For simplicity, can as required total day clothes dosage be distinguished, and gradation is used in during one day.

The amount of application of The compounds of this invention and/or its pharmacologically acceptable salts and frequency adjust according to doctor in charge's judgement, wherein consider some factors, for example the seriousness of patient's age, symptom and size and quilt treatment symptom.Orally administered typical case is advised that every day, the dosage instructions about how to take medicine can contain The compounds of this invention from about 0.01mg/ days to about 2000mg/ days scope.In one embodiment, Orally administered dosage instructions about how to take medicine every day are about 1mg/ days to 1000mg/ days.In another embodiment, Orally administered dosage instructions about how to take medicine every day are about 1mg/ days to 500mg/ days.In another embodiment, Orally administered dosage instructions about how to take medicine every day are about 100mg/ days to 500mg/ days.In another embodiment, Orally administered dosage instructions about how to take medicine every day are about 1mg/ days to 250mg/ days.In another embodiment, Orally administered dosage instructions about how to take medicine every day are about 100mg/ days to 250mg/ days.In another embodiment again, Orally administered dosage instructions about how to take medicine every day are about 1mg/ days to 100mg/ days.In another embodiment again, Orally administered dosage instructions about how to take medicine every day are about 50mg/ days to 100mg/ days.In further embodiment, Orally administered dosage instructions about how to take medicine every day are about 1mg/ days to 50mg/ days.In another embodiment, Orally administered dosage instructions about how to take medicine every day are about 25mg/ days to 50mg/ days.In further embodiment, Orally administered dosage instructions about how to take medicine every day are about 1mg/ days to 25mg/ days.Every day, dosage can be used in single dose, perhaps can be divided into 2 to 4 divided doses and use.

In one aspect, the invention provides a kind of medicine box, it comprises at least a The compounds of this invention for the treatment of significant quantity or pharmacologically acceptable salts, solvate, ester or the prodrug of described compound, and pharmaceutically acceptable carrier, medium or thinner.

In yet another aspect, the invention provides a kind of medicine box, it comprises pharmacologically acceptable salts, solvate, ester or the prodrug of a certain amount of at least a The compounds of this invention or described compound, and a certain amount of at least a anti-cancer therapies of above enumerating and/or other carcinostatic agent, wherein the amount of these two or more compositions can produce the result of treatment that needs.

The invention is not restricted to the scope of the disclosed specific embodiments of embodiment, these embodiment will be as the explanation of some aspects of the present invention, and and on function suitable any embodiment all fall in the scope of the invention.In fact, except shown in this paper and describe those, many modifications of the present invention are conspicuous for those skilled in the relevant art, and will fall in the appended claim scope.

Quoted many reference, their whole disclosures are incorporated this paper into its integral body.

Claims

1. formula I compound or its pharmacologically acceptable salts or ester

Formula I

Wherein:

M is N or N-oxide compound;

T be O, S or-NR ⁴

R ²Be H or alkyl;

Condition is to work as R ¹When being morpholinyl, R is not optional alkoxyl group that replaces or optional the replacement-N (alkyl) ₂

2. the compound of claim 1, wherein said ring A is except the substituting group-NR that shows ²C (=T)-(ring that comprises M, X, Y and Z) and R ³In addition, also can choose wantonly and have described 5-to 6-unit aryl, heterocyclic radical, heterocycloalkenyl or heteroaryl ring, optionally be selected from following substituting group and replace by one or more: halogen, cyano group, hydroxyl, alkoxyl group, aryloxy, alkyl ,-NR ⁴R ⁵, haloalkyl, halogenated alkoxy, nitro, aryl ,-C (=O) R ⁴,-C (=O) OR ⁴,-C (=O) NR ⁴R ⁵,-OC (=O) R ⁴With-NR ⁴C (=O) R ⁴

3. the compound of claim 1, wherein each R ¹Aryl, heterocyclic radical, heterocycloalkenyl and heteroaryl, and-C (=O) N (R ⁴) aryl ,-C (=O) N (R ⁴) heteroaryl ,-C (=O) N (R ⁴) heterocyclic radical ,-C (=O) N (R ⁴) heterocycloalkenyl ,-N (R ⁴) C (=O) aryl ,-N (R ⁴) C (=O) heteroaryl ,-N (R ⁴) C (=O) heterocyclic radical and-N (R ⁴) C (=O) " heterocyclic radical ", " heterocycloalkenyl " in the heterocycloalkenyl, " aryl " and " heteroaryl " part are optional has described 5-to 6-unit cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical, heterocycloalkenyl or a heteroaryl ring, and optionally be selected from following substituting group and replace by one or more: halogen, hydroxyl, alkoxyl group, aryloxy, alkyl ,-NR ⁴R ⁵, haloalkyl, halogenated alkoxy, nitro, aryl, heteroaryl ,-C (=O) R ⁴,-C (=O) OR ⁴,-C (=O) NR ⁴R ⁵,-OC (=O) R ⁴,-NR ⁴C (=O) R ⁴,-O-alkyl-O-alkyl ,-O-alkyl-O-alkyl-O-alkyl ,-O-alkyl-heterocyclic radical ,-S-R ⁴, heterocyclic radical and-S (=O) ₂-R ⁴

4. the compound of claim 1, wherein X, Y and Z are C (R).

5. the compound of claim 1, wherein T is O.

6. the compound of claim 1, wherein encircling A is heteroaryl.

7. the compound of claim 4, wherein encircling A is pyridyl.

8. the compound of claim 1, wherein R is H.

9. the compound of claim 1, wherein R ²Be H.

10. the compound of claim 1, wherein R ³It is heterocyclic radical.

11. the compound of claim 1, wherein said formula I compound are expressed as with Formula Il compound or its pharmacologically acceptable salts or ester:

Formula II

Wherein:

Z ¹Be CH or N;

Z ²Be CH ₂Or NH

R ⁸Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

N is 0,1 or 2.

12. the compound of claim 11, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁶R ⁷Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group ,-O-alkyl-O-alkyl ,-O-alkyl-O-alkyl-O-alkyl ,-O-alkyl-heterocyclic radical ,-S-alkyl, heterocyclic radical ,-C (=O) OH ,-C (=O) the O alkyl ,-S (=O) ₂-heterocyclic radical, halogen and alkyl.

13. the compound of claim 11, wherein Z ¹Be N.

14. the compound of claim 11, wherein Z ¹Be CH.

15. the compound of claim 11, wherein Z ²Be CH ₂

16. the compound of claim 11, wherein Z ²Be NH.

17. the compound of claim 11, wherein Z ¹Be N, and Z ²Be NH.

18. the compound of claim 11, wherein Z ¹Be N and Z ²Be CH ₂

19. the compound of claim 11, wherein Z ¹Be CH and Z ²Be CH ₂

20. the compound of claim 17, wherein n is 0.

21. the compound of claim 18, wherein n is 1.

22. the compound of claim 19, wherein n is 1.

23. the compound of claim 21 or 22, wherein R ⁸Be-NH ₂

24. the compound of claim 11, wherein-NR ⁶R ⁷It is-NHC (=O) aryl.

25. the compound of claim 24, wherein said-NHC (=O) " aryl " in the aryl is optional is selected from following substituting group by one or more and replaces: alkyl, alkoxyl group, halogenated alkoxy, haloalkyl and halogen.

26. the compound of claim 11, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁶R ⁷Heterocyclic radical is optional and benzene or pyridine ring condensed heterocycle base.

27. the compound of claim 11, wherein-NR ⁶R ⁷Be-NH (2-pyrazinyl).

28. the compound of claim 11, wherein-NR ⁶R ⁷Be selected from:

They each is optional substituted.

29. the compound of claim 26 has wherein that described 5-to the 6-unit heterocyclic radical of described optional condensed benzene or pyridine ring is optional to be selected from following substituting group and to replace by one or more: methyl, methoxyl group, 4-piperidyl ,-C (=O) OH ,-C (=O) OCH ₃,-S (=O) ₂-pyrrolidyl ,-S-CH ₃,-S (=O) ₂CH ₃,-O-CH ₂-tetrahydrofuran (THF), fluorine, chlorine ,-CH ₂CH ₂-(1-morpholinyl) ,-OCH ₂CH ₂-(1-morpholinyl) ,-CH ₂CH ₂-N (CH ₃) ₂,-OCH ₂CH ₂OCH ₂CH ₂OCH ₃,-OCH ₂CH ₂OCH ₃With-OCH ₂CH ₂-N (CH ₃) ₂

30. the compound of claim 11, it is selected from:

Or its pharmacologically acceptable salts or ester.

31. the compound of claim 1, its Chinese style I compound is expressed as with following formula IIA:

Formula IIA

Wherein:

Z ¹Be CH or N;

Z ²Be CH ₂Or NH

Each R ²Be H or alkyl independently;

R ^6aBe selected from aryl or heteroaryl;

R ⁸Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

N is 0,1 or 2.

32. the compound of claim 31, wherein Z ¹Be N.

33. the compound of claim 31, wherein Z ¹Be CH.

34. the compound of claim 31, wherein Z ²Be CH ₂

35. the compound of claim 31, wherein Z ²Be NH.

36. the compound of claim 31, wherein Z ¹Be N, and Z ²Be NH.

37. the compound of claim 31, wherein Z ¹Be N and Z ²Be CH ₂

38. the compound of claim 31, wherein Z ¹Be CH and Z ²Be CH ₂

39. the compound of claim 36, wherein n is 0.

40. the compound of claim 37, wherein n is 1.

41. the compound of claim 38, wherein n is 1.

42. the compound of claim 31, wherein R ^6aIt is aryl.

43. the compound of claim 42, wherein said R ^6aAryl is a phenyl.

44. the compound of claim 43, wherein said R ^6aPhenyl is optional to be selected from following substituting group and to replace by one or more: methoxyl group, trifluoromethyl, fluorine and chlorine.

45. the compound of claim 31, it is selected from:

Or its pharmacologically acceptable salts or ester.

46. the compound of claim 1, its Chinese style I compound is expressed as following formula III compound or its pharmacologically acceptable salts or ester:

Formula III

Wherein in formula III:

Z ³Be CH or N;

Z ⁴Be CH ₂Or NH;

R ¹⁰Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

M is 0,1 or 2.

47. the compound of claim 46, wherein optional described R with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁹Aryl or heteroaryl are optional to be selected from following substituting group and to replace by one or more: heterocyclic radical, alkoxyl group, aryl and alkyl.

48. the compound of claim 46, wherein Z ¹Be N.

49. the compound of claim 46, wherein Z ¹Be CH.

50. the compound of claim 46, wherein Z ²Be CH ₂

51. the compound of claim 46, wherein Z ²Be NH.

52. the compound of claim 46, wherein Z ¹Be N, and Z ²Be NH.

53. the compound of claim 46, wherein Z ¹Be N and Z ²Be CH ₂

54. the compound of claim 46, wherein Z ¹Be CH and Z ²Be CH ₂

55. the compound of claim 52, wherein n is 0.

56. the compound of claim 53, wherein n is 1.

57. the compound of claim 54, wherein n is 1.

58. the compound of claim 46, wherein R ⁹It is-C (=O) NH aryl.

59. the compound of claim 58, wherein-C (=O) the described aryl of NH aryl is optional is selected from following substituting group replacement by one or more: halogen, haloalkyl, alkoxyl group, halogenated alkoxy and alkyl.

60. the compound of claim 46, wherein said R ⁹Be aryl or heteroaryl, and be selected from: phenyl, 4-pyridyl, 2-(6-(1-piperazinyl)) pyridyl, benzofuryl, benzothienyl, benzimidazolyl-, benzo (dihydro) furyl, 3-pyridyl, 2-thienyl, 3-thienyl, 5-pyrimidyl, benzopyrrole base, benzo morpholinyl, benzo pyridyl, phenyl, 3-pyrryl and oxazolyl, it is respectively optional naturally substituted.

61. the compound of claim 60, wherein said R ⁹Benzofuryl, benzothienyl, benzimidazolyl-, benzo (dihydro) furyl, benzopyrrole base, benzo morpholinyl and benzo pyridyl are selected from:

They each is optional substituted.

62. the compound of claim 46, wherein optional described R with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ⁹Aryl or heteroaryl are optional to be selected from following substituting group and to replace by one or more: 1-piperazinyl, methoxyl group, methyl, 1-morpholinyl ,-CH ₂-(1-morpholinyl) and phenyl.

63. the compound of claim 46, it is selected from:

Or its pharmacologically acceptable salts or ester.

64. the compound of claim 1, its Chinese style I compound are expressed as with following formula IV compound or its pharmacologically acceptable salts or ester:

Formula IV

Wherein:

Z ⁵Be CH or N;

Z ⁶Be CH ₂Or NH;

R ¹³Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

P is 0,1 or 2.

65. the compound of claim 64, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹¹R ¹²Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group, halogen, alkyl, heterocyclic radical and aryl.

66. the compound of claim 64, wherein Z ⁵Be N.

67. the compound of claim 64, wherein Z ⁵Be CH.

68. the compound of claim 64, wherein Z ⁶Be CH ₂

69. the compound of claim 64, wherein Z ⁶Be NH.

70. the compound of claim 64, wherein Z ⁵Be N, and Z ⁶Be NH.

71. the compound of claim 64, wherein Z ⁵Be N and Z ⁶Be CH ₂

72. the compound of claim 64, wherein Z ⁵Be CH and Z ⁶Be CH ₂

73. the compound of claim 70, wherein p is 0.

74. the compound of claim 71, wherein p is 1.

75. the compound of claim 72, wherein p is 1.

76. the compound of claim 74 or 75, wherein R ¹³Be-NH ₂

77. the compound of claim 64, wherein R ¹¹And R ¹²Be H and alkyl independently.

78. the compound of claim 77, wherein said R ¹¹And R ¹²Alkyl is alkyl-aryl independently.

79. the compound of claim 78, " aryl " of wherein said alkyl-aryl part is optional to be selected from following substituting group and to replace by one or more: halogen and alkoxyl group.

80. the compound of claim 64, wherein R ¹¹And R ¹²Be independently selected from: H, methyl ,-CH ₂-(3-fluorophenyl) ,-CH ₂-(3-p-methoxy-phenyl) ,-CH ₂-phenyl ,-CH ₂CH ₂-phenyl ,-CH ₂CH ₂-(3-p-methoxy-phenyl) and-CH ₂CH ₂-(3-fluorophenyl).

81. the compound of claim 64 is wherein said-NR ¹¹R ¹²Be selected from: pyrrolidyl, piperidyl,

It is respectively optional naturally substituted.

82. the compound of claim 64, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹¹R ¹²Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: methoxyl group, fluorine, chlorine ,-CH ₂CH ₂N (CH ₃) ₂,-OCH ₂CH ₂-(1-morpholinyl), 2-p-methoxy-phenyl, phenyl and 1-pyrrolidyl.

83. the compound of claim 64, it is selected from:

Or its pharmacologically acceptable salts or ester.

84. the compound of claim 1, its Chinese style I compound are expressed as with following formula IV (A) compound or its pharmacologically acceptable salts or ester:

Formula IV (A)

Wherein:

Z ³Be CH or N;

Z ⁴Be CH ₂Or NH;

R ¹⁰Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

M is 0,1 or 2.

85. the compound of claim 84, wherein said R ^9aAryl or heteroaryl, perhaps optional described-N (R with the first heterocyclic radical of described first and second 5-to 6-, aryl or heteroaryl ²)-C (=O) N (R ²)-aryl should " aryl " part, optionally be selected from following substituting group and replace by one or more: heterocyclic radical, heteroaryl, alkoxyl group, alkyl, aryloxy, dialkyl amido, halogen ,-S (=O) ₂Alkyl ,-the S-alkyl ,-C (=O) alkyl ,-NHC (=O) alkyl ,-O-alkyl-cycloalkyl ,-C (=O) N (alkyl) ₂,-NHC (=O) NH (alkyl) and-C (=O) NH (alkyl).

86. the compound of claim 84, wherein Z ¹Be N.

87. the compound of claim 84, wherein Z ¹Be CH.

88. the compound of claim 84, wherein Z ²Be CH ₂

89. the compound of claim 84, wherein Z ²Be NH.

90. the compound of claim 84, wherein Z ¹Be N, and Z ²Be NH.

91. the compound of claim 84, wherein Z ¹Be N and Z ²Be CH ₂

92. the compound of claim 84, wherein Z ¹Be CH and Z ²Be CH ₂

93. the compound of claim 90, wherein n is 0.

94. the compound of claim 91, wherein n is 1.

95. the compound of claim 92, wherein n is 1.

96. the compound of claim 84, wherein said R ^9aAryl or heteroaryl, perhaps optional described-N (R with the first heterocyclic radical of described first and second 5-to 6-, aryl or heteroaryl ²)-C (=O) R ²" aryl " in-aryl part is selected from: phenyl, indyl, furyl, morpholinyl, pyridyl, indazolyl, pyrimidyl, benzofuryl, benzothienyl, benzo pyridyl, benzothiazolyl, pseudoindoyl, benzimidazolyl-, oxazolyl,

It is respectively optional naturally substituted.

97. the compound of claim 85, wherein said R ^9aAryl or heteroaryl, perhaps optional described-N (R with the first heterocyclic radical of described first and second 5-to 6-, aryl or heteroaryl ²)-C (=O) NR ²" aryl " part in the-aryl optional be selected from following substituting group and replace by one or more: 1-pyrrolidyl, methoxyl group, 1-morpholinyl ,-N (CH ₃) ₂, bromine, fluorine, phenoxy group ,-S (=O) ₂CH ₃,-S-CH ₃, methyl, isopropoxy ,-C (=O) OCH ₃,-NH-C (=O)-CH ₃,-O-CH ₂-cyclopropyl ,-C (=O)-N (CH ₂CH ₃) ₂,-NH-C (=O) NHCH ₂CH ₃With-C (=O) NCH ₃

98. the compound of claim 84, it is selected from:

Or its pharmacologically acceptable salts.

99. the compound of claim 1, its Chinese style I compound are expressed as with following formula V compound or its pharmacologically acceptable salts:

Formula V

Wherein:

Z ⁷Be CH or N;

Z ⁸Be CH ₂Or NH;

R ¹⁶Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

Q is 0,1 or 2.

100. the compound of claim 69, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹⁴R ¹⁵Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group, halogen, alkyl and aryl.

101. the compound of claim 99, wherein Z ⁷Be N.

102. the compound of claim 99, wherein Z ⁷Be CH.

103. the compound of claim 99, wherein Z ⁸Be CH ₂

104. the compound of claim 99, wherein Z ⁸Be NH.

105. the compound of claim 99, wherein Z ⁷Be N, and Z ⁸Be NH.

106. the compound of claim 99, wherein Z ⁷Be N and Z ⁸Be CH ₂

107. the compound of claim 99, wherein Z ⁷Be CH and Z ⁸Be CH ₂

108. the compound of claim 105, wherein q is 0.

109. the compound of claim 106, wherein q is 1.

110. the compound of claim 107, wherein q is 1.

111. the compound of claim 109 or 110, wherein R ¹⁶Be-NH ₂

112. the compound of claim 99, wherein-NR ¹⁴R ¹⁵Be benzo-fused tetramethyleneimine, it is optional substituted.

113. the compound of claim 99, it is a following formula: compound

Or its pharmacologically acceptable salts.

114. the compound of claim 1, its Chinese style I compound are expressed as with following formula VI compound or its pharmacologically acceptable salts:

Formula VI

Wherein:

Z ⁹Be CH or N;

Z ¹⁰Be CH ₂Or NH;

R ¹⁹Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

R is 0,1 or 2.

115. the compound of claim 114, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹⁷R ¹⁸Heterocyclic radical is optional to be selected from following substituting group and to replace by one or more: alkoxyl group, halogen, alkyl and aryl.

116. the compound of claim 114, wherein Z ⁹Be N.

117. the compound of claim 114, wherein Z ⁹Be CH.

118. the compound of claim 114, wherein Z ¹⁰Be CH ₂

119. the compound of claim 114, wherein Z ¹⁰Be NH.

120. the compound of claim 114, wherein Z ⁹Be N, and Z ¹⁰Be NH.

121. the compound of claim 114, wherein Z ⁹Be N and Z ¹⁰Be CH ₂

122. the compound of claim 114, wherein Z ⁹Be CH and Z ¹⁰Be CH ₂

123. the compound of claim 120, wherein q is 0.

124. the compound of claim 121, wherein q is 1.

125. the compound of claim 122, wherein q is 1.

126. the compound of claim 124 or 125, wherein R ¹⁹Be-NH ₂

127. the compound of claim 114, wherein-NR ¹⁷R ¹⁸Be selected from:

It is respectively optional naturally substituted.

128. the compound of claim 114, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹³R ¹⁴Heterocyclic radical is optional to be replaced by one or more alkoxy substituents.

129. the compound of claim 128, wherein said alkoxyl group is a methoxyl group.

130. the compound of claim 114, it is selected from:

Or its pharmacologically acceptable salts.

131. the compound of claim 1, its Chinese style I compound are expressed as with following formula VII compound or its pharmacologically acceptable salts:

Formula VII

Wherein:

Z ¹⁰Be CH or N;

Z ¹¹Be CH ₂Or NH;

R ²⁰Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

S is 0,1 or 2.

132. the compound of claim 131, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹⁷R ¹⁸Heteroaryl is optional to be selected from following substituting group and to replace by one or more: heteroaryl and aryl.

133. the compound of claim 131, wherein Z ¹⁰Be N.

134. the compound of claim 131, wherein Z ¹¹Be CH.

135. the compound of claim 131, wherein Z ¹¹Be CH ₂

136. the compound of claim 131, wherein Z ¹¹Be NH.

137. the compound of claim 131, wherein Z ¹⁰Be N, and Z ¹¹Be NH.

138. the compound of claim 131, wherein Z ¹⁰Be N and Z ¹¹Be CH ₂

139. the compound of claim 131, wherein Z ¹⁰Be CH and Z ¹¹Be CH ₂

140. the compound of claim 137, wherein s is 0.

141. the compound of claim 138, wherein s is 1.

142. the compound of claim 139, wherein s is 1.

143. the compound of claim 141 or 142, wherein R ¹⁹Be-NH ₂

144. the compound of claim 131, wherein-NR ¹⁸R ¹⁹Be pyrazolyl, it is optional substituted.

145. the compound of claim 131, wherein optional described-NR with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ¹³R ¹⁴Heteroaryl is optional to be selected from following substituting group and to replace by one or more: optional thienyl that replaces and the optional aryl that replaces.

146. the compound of claim 131, it is selected from:

Or its pharmacologically acceptable salts.

147. the compound of claim 1, its Chinese style I compound are expressed as with following formula VIII compound or its pharmacologically acceptable salts:

Formula VIII

Wherein:

Z ¹¹Be CH or N;

Z ¹²Be CH ₂Or NH;

Each R ²¹Be H or alkyl independently;

R ²³Be selected from alkyl ,-NH ₂,-NH (alkyl) and-N (alkyl) ₂With

T is 0,1 or 2.

148. the compound of claim 148, wherein optional described R with the first heterocyclic radical of described 5-to 6-, aryl or heteroaryl ²²Aryl is optional to be replaced by halogen.

149. the compound of claim 148, wherein Z ¹¹Be N.

150. the compound of claim 148, wherein Z ¹²Be CH.

151. the compound of claim 148, wherein Z ¹²Be CH ₂

152. the compound of claim 148, wherein Z ¹²Be NH.

153. the compound of claim 148, wherein Z ¹¹Be N, and Z ¹²Be NH.

154. the compound of claim 148, wherein Z ¹¹Be N and Z ¹²Be CH ₂

155. the compound of claim 148, wherein Z ¹¹Be CH and Z ¹²Be CH ₂

156. the compound of claim 153, wherein t is 0.

157. the compound of claim 154, wherein t is 1.

158. the compound of claim 155, wherein t is 1.

159. the compound of claim 148, wherein R ²²Be phenyl, it is optional substituted.

160. the compound of claim 148, wherein said compound are following formula: compound or its pharmacologically acceptable salts:

161. be claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 each compound or its pharmacologically acceptable salts or the esters of purified form.

162. pharmaceutical composition, it comprises at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146 for the treatment of significant quantity, 147 and 160 each compound or its pharmacologically acceptable salts or esters, and at least a pharmaceutically acceptable carrier.

163. the pharmaceutical composition of claim 162, it further comprises one or more carcinostatic agents that are different from claim 1 compound.

164. the pharmaceutical composition of claim 163, wherein these one or more carcinostatic agents are selected from: cytostatic agent, cis-platinum, Zorubicin, taxotere, taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol, docetaxel, Ai Boxi ketone, tamoxifen, 5 FU 5 fluorouracil, Rheumatrex, Temozolomide, endoxan, SCH 66336, R115777, L778123, BMS 214662,

The antibody of EGFR,

Intron, ara-C, Zorubicin, endoxan, gemcitabine, uracil mustard, mustargen, ifosfamide, L-PAM, Chlorambucil, pipobroman, Persistol, triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, pentostatin, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Zorubicin, epirubicin, idarubicin, mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide 17 alpha-acetylenes estradiol, stilboestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium, Emcyt, the Zytron acetic ester, Leuprolide, Drogenil, toremifene, goserelin, cis-platinum, carboplatin, hydroxyurea, Amsiacrine, procarbazine, mitotane, mitoxantrone, L-tetramisole, nvelbine, Anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, white arsenic, xeloda, vinorelbine, porfimer;

Liposome, thio-tepa, hexamethyl melamine, L-PAM, trastuzumab, Lerozole, fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Doxil, Ontak, Deposyt, Mylotarg, Campath, Celebrex, Sutent, Aranesp, Neupogen, Neulasta, Kepivance, SU11248 and PTK787.

165. suppress one or more cell cycle protein dependent kinases or treat one or more and the method for cell cycle protein dependent kinase diseases associated, it comprises to this at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146 that suppresses patient's administering therapeutic significant quantity of needs, 147 and 160 each compound or its pharmacologically acceptable salts or esters are arranged.

166. treat the method for one or more and cell cycle protein dependent kinase diseases associated, it comprises to the administration that these treatment needs are arranged

A certain amount of first compound, this first compound are claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 each compound or its pharmacologically acceptable salts or esters; With

A certain amount of at least a second compound, this second compound are to be different from claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 each the carcinostatic agents of compound;

Wherein the amount of first compound and second compound can produce result of treatment.

167. the method for claim 166, wherein this cell cycle protein dependent kinase is CDK1.

168. the method for claim 166, wherein this cell cycle protein dependent kinase is CDK2.

169. the method for claim 166, wherein this disease is selected from:

Bladder cancer, breast cancer, colorectal carcinoma, kidney, liver cancer, lung cancer, small cell lung cancer, nonsmall-cell lung cancer, head and neck cancer, esophagus cancer, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, cancer of the stomach, cervical cancer, thyroid carcinoma, prostate cancer and skin carcinoma comprise squamous cell carcinoma;

Leukemia, acute lymphoblastic leukemia, lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphomas, non-Hodgkin lymphomas, galley proof cell lymphoma, adventitial cell lymphoma, bone marrow cell carcinoma and Burkett lymphomas;

Acute and chronic lymphocytic leukemia, myelodysplastic syndrome and progranulocyte leukemia;

Fibrosarcoma, rhabdosarcoma;

Astrocytoma, neuroblastoma, neurospongioma and schwannoma;

Melanoma, spermocytoma, teratocarcinoma, osteosarcoma, different skin painted (xenoderomapigmentosum), molluscum pseudocarcinomatosum (keratoctanthoma), Tiroidina follicular carcinoma and Kaposi sarcoma.

170. the method for claim 166, it further comprises radiotherapy.

171. the method for claim 167, wherein this carcinostatic agent be selected from cytostatic agent, cis-platinum, Zorubicin, taxotere, taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol, docetaxel, Ai Boxi ketone, tamoxifen, 5 FU 5 fluorouracil, Rheumatrex, Temozolomide, endoxan, SCH 66336, R115777, L778123, BMS 214662, The antibody of EGFR,

Intron, ara-C, AC, gemcitabine, uracil mustard, mustargen, ifosfamide, L-PAM, Chlorambucil, pipobroman, Persistol, triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, oxaliplatin, formyl tetrahydrofolic acid, ELOXATIN ^TMPentostatin, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Zorubicin, epirubicin, idarubicin, mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide 17 alpha-acetylenes estradiol, stilboestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium, Emcyt, the Zytron acetic ester, Leuprolide, Drogenil, toremifene, goserelin, cis-platinum, carboplatin, hydroxyurea, Amsiacrine, procarbazine, mitotane, mitoxantrone, L-tetramisole, nvelbine, Anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, white arsenic, xeloda, vinorelbine, porfimer;

172. in the patient who needs is arranged, suppress the kinase whose method in one or more check points, perhaps treatment is with one or more check point kinases diseases associated or alleviate the method for this disease process, and this method comprises at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146 of this patient's administering therapeutic significant quantity, 147 and 160 each compound or its pharmacologically acceptable salts or esters.

173. treat the method for one or more and check point kinases diseases associated, it comprises to the administration that these treatment needs are arranged

A certain amount of at least a second compound, this second compound is different from claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 compound, and this second compound is a carcinostatic agent;

174. the method for claim 173, wherein carcinostatic agent be selected from cytostatic agent, cis-platinum, Zorubicin, taxotere, taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol, docetaxel, Ai Boxi ketone, tamoxifen, 5 FU 5 fluorouracil, Rheumatrex, Temozolomide, endoxan, SCH 66336, R115777, L778123, BMS 214662,

The antibody of EGFR,

175. treatment and one or more check point kinases diseases associated or delay the method for this progression of disease in the patient who needs is arranged, it comprises the pharmaceutical composition of the claim 162 of administering therapeutic significant quantity.

176. claim 172,173 or 175 method, wherein this check point kinases is Chk1.

177. claim 172,173 or 175 method, wherein this check point kinases is Chk2.

178. in the patient who needs is arranged, suppress the method for one or more Tyrosylprotein kinases, perhaps treatment is with one or more Tyrosylprotein kinase diseases associated or alleviate the method for this disease process, and this method comprises at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146 of this patient's administering therapeutic significant quantity, 147 and 160 each compound or its pharmacologically acceptable salts or esters.

179. treat the method for one or more and Tyrosylprotein kinase diseases associated, it comprises to the administration that these treatment needs are arranged

180. treatment and one or more Tyrosylprotein kinase diseases associated or delay the method for this progression of disease in the patient who needs is arranged, it comprises the medical composition of administering therapeutic significant quantity, and it comprises at least a pharmaceutically acceptable carrier and at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 each compound or its pharmacologically acceptable salts or esters.

181. the method for claim 180, wherein this Tyrosylprotein kinase is selected from VEGF-R2, EGFR, HER2, SRC, JAK and TEK.

182. the method for claim 180, wherein this Tyrosylprotein kinase is VEGF-R2.

183. the method for claim 180, wherein this Tyrosylprotein kinase is EGFR.

184. in the patient who needs is arranged, suppress the kinase whose method of one or more Pim-1, perhaps treatment is with one or more Pim-1 kinases diseases associated or alleviate the method for this disease process, and this method comprises at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146 of this patient's administering therapeutic significant quantity, 147 and 160 each compound or its pharmacologically acceptable salts or esters.

185. treat the method for one or more and Pim-1 kinases diseases associated, perhaps treatment is with one or more Pim-1 kinases diseases associated or alleviate the method for this disease, this method comprises that to a certain amount of first compound of administration that this treatment needs are arranged this first compound is claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 each compound or its pharmacologically acceptable salts or esters; And a certain amount of at least a second compound, this second compound is different from claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 compound, this second compound is a carcinostatic agent, and wherein the amount of first compound and second compound can produce result of treatment.

186. treatment method for cancer, this method comprise at least a claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 each the compound or pharmaceutically acceptable salt thereof or the esters of administering therapeutic significant quantity.

187. the method for claim 186, wherein said cancer is selected from:

Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, hodgkin's lymphomas, non-Hodgkin lymphomas, galley proof cell lymphoma, adventitial cell lymphoma, bone marrow cell carcinoma and Burkett lymphomas;

Fibrosarcoma, rhabdosarcoma;

Head and neck cancer, mantle cell lymphoma, myelomatosis;

Astrocytoma, neuroblastoma, neurospongioma and schwannoma;

188. the treatment method for cancer, it comprises to the administration that these treatment needs are arranged

A certain amount of at least a second compound, this second compound is different from claim 1,11,30,31,45,46,63,64,83,84,98,99,113,114,130,131,146,147 and 160 compound, and described second compound is a carcinostatic agent;

Wherein the amount of this first compound and described second compound can produce result of treatment.

189. the method for claim 188, it further comprises radiotherapy.

190. the method for claim 188, wherein said carcinostatic agent be selected from cytostatic agent, cis-platinum, Zorubicin, taxotere, taxol, Etoposide, Rinotecan, camptostar, Hycamtin, taxol, docetaxel, Ai Boxi ketone, tamoxifen, 5 FU 5 fluorouracil, Rheumatrex, Temozolomide, endoxan, SCH 66336, R115777, L778123, BMS 214662,

The antibody of EGFR,

Intron, ara-C, Zorubicin, endoxan, gemcitabine, uracil mustard, mustargen, ifosfamide, L-PAM, Chlorambucil, pipobroman, Persistol, triethylene sulfo-phosphamidon, busulfan, carmustine, lomustine, streptozocin, dacarbazine, fluorodeoxyuridine, cytosine arabinoside, Ismipur, 6-sulfenyl guanine, fludarabine phosphate, pentostatin, vinealeucoblastine(VLB), vincristine(VCR), vindesine, bleomycin, gengshengmeisu, daunorubicin, Zorubicin, epirubicin, idarubicin, mithramycin, deoxidation is formycin altogether, Mitomycin-C, the altheine enzyme, teniposide 17 alpha-acetylenes estradiol, stilboestrol, testosterone, prednisone, FL, dromostanolone propionate, testolactone, the acetate megestrol, medrat, methyltestosterone, Prednisolone Acetate, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimidium, Emcyt, the Zytron acetic ester, Leuprolide, Drogenil, toremifene, goserelin, cis-platinum, carboplatin, hydroxyurea, Amsiacrine, procarbazine, mitotane, mitoxantrone, L-tetramisole, nvelbine, Anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethyl melamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, white arsenic, xeloda, vinorelbine, porfimer (Porfimer);

Liposome, thio-tepa, hexamethyl melamine, L-PAM, trastuzumab, Lerozole, fulvestrant, Exemestane, fulvestrant, Ifosfomide, Rituximab, C225, Doxil, Ontak, Deposyt, Mylotarg, Campath, Celebrex, Sutent, Aranesp, Neupogen, Neulasta, Kepivance, SU11248 and PTK787.